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Health 32 > Cancer (genome) > Flashcards

Cancer (genome) Flashcards

1
Q

one reason why developed countries might have higher prevalence of cancer?

A

better technology for early detection

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2
Q

name one secondary cancer that might occur in women that have breast cancer?

A

lung

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3
Q

true or false: cancer is most common in older people and majority of cases occurs in people that are aged 60 or over?

A

true

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4
Q

What cells do cancers arise from?

A

normal ones

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5
Q

What are the 3 categories of cancers based on the type of cell they develop from?

A
  • carcinoma
  • sarcoma
  • haematological malignancies
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6
Q

carcinomas are the most common tye of cancer and developed from what cell types and where would you find them?

A

epithelial cells in lung, colon and prostate etc

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7
Q

sarcomas are derived from what type of non epithelial cells? (1% of all cancer but more aggressive)

A

mesenchymal

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8
Q

What are examples of haematological malignancies and what percentage of cancers do they make up?

A

lymphoma and leukemia, 17%

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9
Q

What are the types of cancers based on their pattern of growth?

A
  • benign
  • malignant
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10
Q

name given to cancers or tumours whose growth is local and do not invade the surrounding organs and tissue?

A

benign

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11
Q

What is a malignant tumor?

A

invasion of neighbouring tissue w potential to metastasise

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12
Q

What is meant by metastasis?

A

development of secondary malignant growths at a distance from a primary site of cancer.

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13
Q

one site which is common for benign tumours?

A

brain

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14
Q

what might be the consequence of a brain tumour close to the optic nerve?

A

loss of sight

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15
Q

example of a benign tumour that can become malignant?

A

breast

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16
Q

are in situ carcinomas malignant or benign?

A

benign

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17
Q

90% of cancer deaths are caused by metastasis. where does colon cancer metastasize and where might melanoma metastisize?

A

colon cancer in liver and melanoma in lung

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18
Q

What are characteristics of a cancer cell?

A
  • immortal
  • loss of contact inhibition
  • high saturation density
  • reduced requirement for mitogenic growth factors
  • inability to halt proliferation in response to deprivation of growth factors
  • altered morphology
  • anchorage independent
  • tumorigenicity
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19
Q

What is meant by loss of contact inhibition?

A

cancer cells do not stop growing when they contact other cells, like healthy ones do

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20
Q

What is meant by cancer cells being anchorage independent?

A

they can adapt to different environments

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21
Q

What is meant by tumorigenicity?

A

when injecting cancer cells into mice, a tumour will form and able to live longer

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22
Q

What is an oncogene?

A

a mutated gene with the potential to cause cancer

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23
Q

What is a proto-oncogene?

A

normal gene that can become oncogene due to mutations or increased expression

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24
Q

whats the product of an oncogene?

A

tumour inducing agent

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25
Q

what types of proteins are usually proto oncogenes?

A

proteins involved in:

  • promoting entry into cell cycle e.g. receptor-tyrosine kinases, Ras
  • protection from apoptosis e.g. Bcl2
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26
Q

What are tumour suppressor genes and what is their status in cancer cells?

A
  • anti-growth genes
  • inactivated in cancer cells, both copies require inactivation of growth control to be lost
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27
Q

What are examples of tumour suppressor genes?

A

RB
p53

= examples that are proteins controlling cell cycle, particularly entry into G1

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28
Q

Where within the cell cycle do tumour suppressor genes fit?

A

between G0 and S, before apoptosis

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29
Q

what do protooncogenes enable, and suppress around G phase of cell cycle?

A

promote cell prolif, but if it mutates… can turn into oncogene -> uncontnrolled cell death. apoptosis

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30
Q

during cell prolif, cell undergoes DNA replication and this can -> mistakes due to elaborate process. what do DNA repair genes do?

A

can help fix this/ result in apoptsis
but these mutations can also present in these genes = mistakes dont get fixed
eventually -> metastasis + secondary tumours

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31
Q

how can familial adenomatous polyposis lead to cancer?

A

people inherit mutant form of tumour suppressor gene APC, prone to thousands of polyps, which can progress to become cancerous

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32
Q

different tumours have different combinations of mutations, what is usually the first tumour suppressor to be lost?

A

APC

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33
Q

whats the start of screening to monitor tumour progression?

A

hyperplastic epithelium point
(after loss of APC)

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34
Q

hallmarks of cancer outlines the different characteristics of cancer cells. what are they?

A

sustaining proliferative signalling,
evading growth suppressors,
activating invasion and metastasis,
enabling replicative immortality,
induce angiogenesis
resist cell death

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35
Q

What are the emerging hallmarks of cancer? 2

A

deregulating cellular energetics
avoiding immune destruction

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36
Q

What are the enabling characteristics of cancer? 2

A

genome instability and mutation
tumout promoting inflammation

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37
Q

what are 4 general areas/ broad causes of cancer?

A
  • genetic predisposition
  • lifestyle
  • environmental causes
  • micro-organisms
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38
Q

what are some environmental causes of cancer?

A

high radioactive environment
exposure to sun

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39
Q

how many cancers occur due to inheritence of faulty genes

A

relatively small num
5-10%

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40
Q

most cancers due to XX genes rather than oncogenes

A

tumour suppressor genes

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41
Q

tumours promote inflammation hence using what type of drug can reduce some of these in combination with other drugs?

A

anti inflammatories

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42
Q

name 3 types of cancer that can be hereditary?

A

breast, colon and thyroid

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43
Q

3 tumour suppressor genes involved in breast cancer?

A

BRCA1,2, p53

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44
Q

tumout suppressor gene in colon cancer?

A

APC

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45
Q

what are the lifestyle risk factors for cancer?

A

diet, excercise, alcohol, smoking, obesity

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46
Q

name one infective agent and the cancer that it can cause?

A

HPV and cervical cancer

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47
Q

what can micro-organism epstein barr virus associated w glandular fever, cause?

A

some lymphomas - cancer of lymph gland

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48
Q

what can micro organism HIV cause? cancers

A

kaposi sarcoma

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49
Q

if infection w H. Pylori is left untreated, may lead to what cancer?

A

stomach

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50
Q

what is key in successful treatment?

A

early diagnosis

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51
Q

name some environmental or occupational substances that can cause cancer?

A

asbestos

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52
Q

some cancers are difficult to detect early and thus more difficult to treat., what screening programmes exist in the UK for early detection?

A

mammograms for breast cancer women above 50, cervical smear tests and bowel cancer screen for men and women above 74

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53
Q

what are the 3 broad areas of cancer treatment?

A

surgery, chemo and radiotherapy

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54
Q

why may chemo drugs (drugs that target rapidly dividing) be given before surgery?

A

if tumour too big to remove
or sometimes its attached to diff cells= harder to remove

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55
Q

reason for so many SEs seen with chemo? hair loss, nausea, loss of appetite, weight loss, anaemia

A

suppressing immunity of whole body

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56
Q

how radiotherapy works

A

cause DNA damage and cell death

can be directed at tumour so reduce damage to other tissues and organs

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57
Q

what are some of the new treatments that are being developed? what do they target?

A
  • target oncoproteins with specific drugs,
  • angiogenesis inhibitors
  • immune therapy
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58
Q

what do angiogenesis inhibitors do?

A

inhibit the formation of vessels that feed the tumour

tumour deprived of nutrients, cant grow

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59
Q

immune therapy drugs use body immune system to fight cancer, a drawback is…

A

they have bad SEs

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60
Q

5 cancer treatment drug types?

A

alkylating agents
antimetabolites
anti-microtubule agents
topoisomerase inhibs
cytotoxic antibiotics

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61
Q

what is the moa of alkalating agents?
eg nitrogen mustards
tetrazines
cisplatins

A

alkalation and damage of DNA

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62
Q

what is the moa of antimetabolites?
eg antifolates eg MTX

A

molecules impede DNA and RNA synthesis
similar struc to building blocks of both

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63
Q

what is the moa of anti microtubule agents?

vinca alkaloids eg vincristine
taxanes eg paclitaxel

A

prevent assembly of microtubules disrupts mitotic spindle and mitosis
or
prevent disassembly of microtubules disrupts mitotic spindle and mitosis

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64
Q

what is the moa of topoisomerase inhibitors?
eg irinotecan, topotecan

A

target topoisomerase enzymes,
disrupt dna replication and rna synthesis

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65
Q

what is the moa of cytotoxic antibiotics?
anthracyclines eg doxorubicin

A

intercalates with dna and generates free radicals

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66
Q

what are cons of IV infusion chemo?

A

long, uncomfortable and infusion reactions

GI ses

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67
Q

why are women encouraged to take right contraceptives during cancer treatment drug therapy?

A

they may cause infertility

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68
Q

what is use of neoadjuvant therapy before surgery?

A

reduce tumour size

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69
Q

adjuvant therapy may-may not be given after surgery. use of it?

A

to reduce chance of recurrence of metastases

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70
Q

drug class of nitrogen mustards, tetrazines and cisplatins?

A

alkalating agents

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71
Q

methotrexate is an anti folate drug belonging to what drug class?

A

antimetabolite

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72
Q

vincristine is a vinca alkaloid belonging to what drug class?

A

anti microtubule agent

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73
Q

paclitaxel is a taxane, what is its drug class?

A

anti microtubule agent

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74
Q

name two topoisomerase inhibitors?

A

ironotecan and topotecan

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75
Q

name one anthracycline cytotoxic antibiotic?

A

doxorubicin

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76
Q

DNA damage and repair…….

genome instability is a hallmark of tumour cells/ cancer that tumors have to develop. what does this mean?

A

= increased propensity to develop genomic alterations

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77
Q

true or false: mutations in genes involved in suppressing genome stability are a major cause of hereditary and sporadic cancer ?

A

true

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78
Q

cells maintain their genome through DNA repair after a variety of insult due to normal function. What 2 types of damage might occur?

A

intrinsic and exogenous

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79
Q

example of exogenous damage?

A

chemical mutagens

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80
Q

give 3 examples of intrinsic damage?

A

normal dna replication
spontaneous base damage
VDJ recombination

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81
Q

types of radiation that might cause dna damage?

A

UV or ionising

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82
Q

what might the inability to resolve dna lesions lead to?

A

genome instability

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83
Q

true or false: inherited mutations in DNA repair are closely linked to genome instability cancer?

A

true

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84
Q

affect of intrinsic DNA damage to DNA lesion?

A

base damage
base mismatches
insertions
deletions
DNA strand breaks

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85
Q

affect of chemical agent damage to DNA lesion? (bad)

A

base modifications
abasic sites
dna strand breakas, adducts, cross links

I
I
V
genome instability

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86
Q

affect of radiation DNA damage to DNA lesion?

A

pyrimidine dimers
base modifications
abasic sites
dna strand breaks

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87
Q

what prevents dna damage leading togenome instability?

A

dna damage response

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88
Q

outline the mutator hypothesis?
(what mutations in dna repair genes lead to)

A
  • genome instability in people in precancerous lesions
  • drives tumourigenesis by increasing spontaneous mutation rate
    –> mutations in oncogenes/ tumour suppressors
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89
Q

how may base alkylation occur?

A

happens spontaneously or through exposure to chemical mutagens (eg benzoate pyrene)

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90
Q

what type of dna repair pathway repairs base alkylation due to instrinsic or chemical agent damage?

A

single strand break repair

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91
Q

what is meant by direct repair in the context of single strand break repair?

A

MGMT or ALKBH work directly on the base to reverse alkylation

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92
Q

what detects double strand break or abnormal DNA replication?

A

sensor molecules MRN complex or RPA molecule

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93
Q

MRN/ RPA pass signal of damage to transducers (ATM OR ATR/ATRIP), what does this allow the activation of?

A

recruitment of multifunctional mediator proteins

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94
Q

what is the term given to the molecules that carry out the checkpoint arrest or DNA repair, when there is a double strand break or abnormal DNA replication?

A

effectors:
Chk2/p53
chk1

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95
Q

DNA is very prevalent and dangerous thus cells must respond very quickly and effectively with good accuracy to prevent genome instability. What does the DNA repair pathway include to spread the repair signal across mega bases of DNA surrounding the break?

A

extra amplification, phosphorylation of histone variant that surround the break

H2AX

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96
Q

what type of repair removes simple alkylation and oxidative damage?

A

BER

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97
Q

what type of repair removes bulky helix distorting lesions (UV-C)?

A

NER

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98
Q

what does MMR remove?

A

mismatched bases

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99
Q

give 3 pathways that repair the majority of single strand breaks ?

A

NER, BER and MMR

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100
Q

are single or double strand breaks more dangerous?

A

double

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101
Q

double strand breaks in both backbones of DNA molecule is sufficient to kill a cell, true or false?

A

true

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102
Q

what type of damage might cause double strand breaks?

A

hard to replicate areas, immune system recombination events, chemo and radiation

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103
Q

what 2 main pathways repair double stranded breaks?

A

HRR and NHEJ

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104
Q

in what way does NHEJ repair double strand breaks?

A

broken ends are directly ligated together

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105
Q

what repair pathway performs the majority of DNA DSB repair?

A

NHEJ

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106
Q

what does HRR require for DSB repair?

A

homologous template of sister chromatids

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107
Q

why does HER pathway only occur in the S or G2 phases of the cell cycle?
after replication

A

requires a sister chromatid

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108
Q

is HRR or NEHJ faster?

A

NHEJ

HRR perhaps more accurate but more time consuming

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109
Q

genome instability drives the loss of tumour suppressor genes and the gain of oncogenes which leads to carcinoma. What is the reason behind this?

A

inherited MMR defects
or gene inactivation/ promoter hypermethylation

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110
Q

give 3 ways in which tumoural cells are more susceptible to therapies?

A

loss of DDR pathway/s,
increased levels of replication
increased levels of endogenous DNA damage

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111
Q

the 3 ways/ characteristics that make tumoural cells susceptible to therapies include:
loss of DDR pathway/s,
increased levels of replication
increased levels of endogenous DNA damage

give 2 examples of when these can be exploited to kill cancer cells?

A
  1. loss of BRCA1 (HR pathway), use PARPi Olaparib to induce legions requiring HR for repair -> cell death
  2. use ATRi to sensitise cells to replic problems -> cell death
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112
Q

Synthetic lethality and treatment……

what is meant by synthetic lethality?

A

exploiting mutations in cancer cells… using inhibitor against a complementary pathway to exploit a pre-existing genetic defect

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113
Q

explain the concept of synthetic lethality and the differences in normal and cancer cells?

A
  • normal cells have both repair pathways A and B
  • cancer cells have a functional pathway B but weakened pathway A
  • introducing a pathway B inhibitor means both pathways are compromised for cancer cells but normal cells can rely on pathway A (compensates)
  • normal cells survive and cancer cells die
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114
Q

mutations in dna repair factors BRCA1/BRCA2 increase the risk of developing what 2 types of cancer?

A

breast and ovarian

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115
Q

mutations in BRCA1/BRCA2 mean that cancers are susceptible to targeted therapies eg?

A

PARP inhibitors

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116
Q

give two tumour areas/ cancers that PARPi can be used to target aside from breast and ovarian?

A

tumours w similar mutations eg prostate, leukemia

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117
Q

PARP acts to repair many different types of DNA damage. if inhibited the damage that is created relies on BRCA1/2 on repair. What effect will PARPi have on cells that are normal vs cancer cells (that are BRCA1/2 deficient)?

A

normal cells survive and cancer cells die

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118
Q

BRCA 1 and 2 are key factors in which DSB repair pathway?

A

HRR

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119
Q

PARP inhibitors are lethal for cells that lack BRCA1/2 and fine for those that have it, true or false?

A

true

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120
Q

PARPis inhibit PARP thus leading to what damage?

A

DNA damage and cell death

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121
Q

2 most likely pathways that PARPi work?

A

PARP functions in BER
PARP trapping in DNA damage

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122
Q

what PARPi would you give for genomic BRCA mutation treated with chemo for ovarian cancer?

A

Olaparib

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123
Q

what PARPi would be appropriate for metastatic breast cancer with genomic BRCA mutations?

A

Olaparib

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124
Q

what 2 PARPi have been approved for clinical use?

A

olaparib and niraparib

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125
Q

what PARPi would be appropriate for HR defective tumours in advanced ovarian/fallopian & primary peritoneal cancer?

A

niraparib

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126
Q

what PARPi would be appropriate for maintenance treatment for genomic BRCA-mutated cancers such as pancreatic?

A

olaparib

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127
Q

BRCA1/2 mutations give HRR defiency and sensitivity to platinum, why is this?

A

bc platinum damage requires HRR to repair

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128
Q

why are platinum sensitive tumours more responsive to PARPi?

A

platinum sensitivity correlates to HRR function

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129
Q

PARPi are a potential treatment for radio and immune therapy such as PDL1 inhibition, true or false?

A

true

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130
Q

many tumours have ATM mutations which regulates the entire response to DNA damage. these mutations lead to loss of function of pathway thus the cells become reliant on ATR (sister kinase to ATM) which acts on different types of damage. Would would happen to these cells if given ATRi?

A

cell death as dont have functional ATM

need ATM + ATR. like BRCA1,2

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131
Q

activated oncogenes via mutation or over expression drives dys regulated replication and thus replication stress. ATR prevents replication stress. If ATR is inhibited what effect will this have on activated oncogenes?

A

anything with activated oncogene susceptible to cell death via ATRi

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132
Q

there are currently no ATRi validated for clinical use, true or false?

A

true

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133
Q

why is effective DNA repair a 2 sided coin essentially?

A

can promote tumourgenesis + gives cells intrinsic weaknesses we can exploit using targeted therapies to kill cancer cells

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134
Q

Cell proliferation & oncogenes…..

cancer results from defects in the what?

A

regulatory pathways that allow escape from normal controls of cell prolif, diff, death

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135
Q

there are 3 points in the regulation pathway which may defect and result in cancer what are they?

A

driving proliferation
blocking quiescence/ differentiation
inducing apoptosis

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136
Q

what are the steps in controll of cell survival and proliferation that -> can have a knock on effect on DNA replication,cell cycle, mitosis etc.

A

growth factors in ECM bind to their receptors on cell memb
activate intracellular signalling
can cause change in transcription in nucleus->.

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137
Q

when growth factors in the extracellular space such as EGF and PDGF bind to their receptors embedded in cell membranes (eg cytokine receptor) , what is activated?

A

intracellular signalling pathways

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138
Q

what is the end result of activating any of the intracellular signalling pathways?

A

cause a change in gene transcription in nucleus

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139
Q

name some processes that a change in gene transcription can have an effect on?

A

DNA replication, cell cycle, mitosis

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140
Q

how can control of cell survival and proliferation be changed during cancer?

A

can be deregulated -> drives tumourgenesis

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141
Q

name of normal genes that control proliferation/ growth that become X due to mutations or increased expression/ translocation of gene to an area of the genome where it shouldnt be?

A

protooncogene
to oncogene

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142
Q

do oncogenes induce tumour genesis directly?

A

yes

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143
Q

gene amplification is one process by which protocogenes can become oncogenic. How are these amplified in tumours?

A

duplicated, more gene copies so higher level of expression

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144
Q

give an example cancer where protooncogenes become oncogenic by gene amplification?

A

HER2 in breast cancer

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145
Q

give 2 examples other than gene amplification/overexpression that drive proto-oncogenes -> oncogenes and example cancers

A

translocations -> hybrid oncogenes (BCR-ABL in leukemia)

missense mutations -> consecutively sctive protein (EGFR in lung cancer, B-RAF in melanoma)

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146
Q

what type of receptors (the mols that transmit extracellular signals into cell) due growth factors usually bind to?

A

receptor tyrosine kinases

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147
Q

what effects does growth factor binding have on receptor tyrosine kinases themselves? 4

A

conformational change,
dimerisation,
activation of cytoplasmic domain
and trans phosphorylation

148
Q

what are the receptors for:
- platelet derived GF
- epidermal GF
- insulin
- insulin-ike GF
(- transforming GF (TGFa and b))

A

-PDGF receptor
- EGF receptor
- insulin receptor
- IGF receptor (insulin like GF)

149
Q

what effect does phosphorylation on RTK have?

A

facilitates interactions between recruited proteins and other factors in membrane hence transmits signal downstream

150
Q

autophosphorylation further activates TK activity, which leads to what in terms of receptor and interactions?

A

cytoplasmic proteins bind to the phosphorylated receptro

  • interactions between proteins/ w other factors at plasma memb
    and also some recruited proteins become activated by tyrosine-phosphorylation
151
Q

binding of cytoplasmic proteins to phosphorylated receptor allows what?

A

downstream signalling

152
Q

what are the different pathways that proliferate/ become activated when receptor TK activated? (drives cell prolif and gene transcription)

A

phospholipase Cy
PI/lipid signalling pathways
serine/ threonine kinase cascades
Ras
other TKs eg c-src

153
Q

true/false, theres considerable overlap in cytoplasmic signalling pathways + early response genes, activated by diff GFs (eg PDGF, FGF receptors)

A

true
so pathways they activate are conserved between diff receptors

154
Q

what effect does amino acid changes or partial deletions have on receptor tyrosine kinases? 3

A

constitutive tyrosine kinase activity,
loss of receptor domain
growth independent signalling

155
Q

what is GF independant signalling?

A

dont need ligand/ GF to activate it

156
Q

mutations in TK domain of EGFR in NSCLC and v-erbB (oncogene of avian erythroblastosis virus) = 2 examples of aa changes/ partial deletions in RTK -> cancer
what do these lead to?

A

signalling without GF

157
Q

what effect does gene amplification or over expression have on receptor tyrosine kinases themselves? 2

A

increased expression of normal receptors and overexpression of aberrant receptors

158
Q

what is the reason behind gene amplification/ overexpression?

A

the receptors are normal (not mutated) so still regulated in some manner but may get 10000x mols instead of just 10x etc

cell is more sensitive to GF than normal cell

159
Q

amplification of EGFR in glioblastoma, breast, lung cancer & erbB/HER2/neu overexpressed in breast cancer = 2 examples of gene amplification/ overexpression in RTK -> cancer
what do these lead to?

A

increased signalling

160
Q

what is the difference between amino acid changes/partial changes and gene amplification/overexpression in terms of signalling of receptor tyrosine kinases?

A

first results in signalling without growth factors and is mutation
second results in increased signalling and is not a mutation

161
Q

what is meant by HER2 positive?

A

duplication of amplification of HER2

162
Q

does increased copy number of HER2 have a better or poorer prognosis in breast cancer?

A

poorer

163
Q

what family of RTKs does HER2 belong to?

A

EGFR

164
Q

what type of kinase is BCR-ABL?

A

fusion

165
Q

BCR is a tyrosine kinase. ABL is another tyrosine kinase, how is it different?

A

promotes cell survival and cell growth upon activation

166
Q

what do BCR and ABL (2 distinct proteins/ kinases) mediate?

A

intracellular signalling pathway

167
Q

role of BCR?

A

a TK and GTP regulator

168
Q

is BCR or ABL made of:
- coiled-coil motif
- Ser-Thr kinase
- GEF
- GAP

A

BCR

169
Q

is BCR or ABL made of:
- membrane attachment
- inhibitory/regulatory SH3,2
- Tyr kinase
- DNA binding sites

A

ABL

170
Q

in mainly leukaemias there is a BCR-ABL fusion. What domain is lost in BCR and what domain is lost in ABL?

A

GTP regulating in BCR
and inhibitory in ABL

171
Q

in BCR-ABL fusion, BCR inhibits SH3 regulatory domain leading to what?

A

constitutive kinase activity
… + dirves cell proliferation

172
Q

a translocation between chromosomes 9 and 22 between BCR and ABL results in the formation of what chromosome?

A

philadelphia

173
Q

what is the most common cancer that BCR-ABL fusion is seen in?

A

CML

174
Q

the 3 genes: h-ras, k-ras, n-ras belong to which family?

A

RAS

175
Q

RAS genes are the most commonly mutated oncogenes. What is GDP replaced with upon a signal to allow signal transduction and proliferation downstream?

A

GTP

176
Q

in cancer reduced GTPase activity is lost, what does this mean in cancer?

A

GTP cannot be broken into its inactive form GDP, so uncontrolled signal transduction

177
Q

RAS mutations in cancer always involve what type of mutation at specific sites (codons 12, 13 or 61)

A

point mutations

178
Q

give 2 groups of people that would be more likely to get G/T transversion (GLY to VAL) point mutations?

A

smokers or works with occupational carcinogen exposure
as typical of carcinogen-induced mutations in those

179
Q

RAS signals are transduced down to the nucleus. BRAF is a protein involved in this protein and is mutated in many cancers and in a high % of which type of cancer?

A

melanomas 60%

180
Q

BRAF and cancer: sequenced genes in RAS/RAF/MEK/ERK/MAPK signalling pathway. initially sequenced genes from hm assorted cancer cell lines?
in experiment

A

15
3 mutations in BRAF (one of 3 RAF genes)

181
Q

RAF exists as a family of 3 genes that helps drive activity of RAS and drive proliferation. mutations are common in melanoma and other tumours. What effect do these mutations have on RAF?

A

stimulate activity and increase proliferation

182
Q

B-RAF mutations clustered in conserved regions. what 2 types of mutations are most common? and whats happening

A

V600D & E
- cell prolif not inhibited by blocking RAS action i.e. mutants stimulate proliferation independant of upstream signalling

183
Q

EGFR and HER-2 are both what?

A

receptors

184
Q

RAS and RAF are both what?

A

downstream signalling mols thta drive signalling to nucleus

185
Q

what pathway does BCR-ABL have a role in?

A

RAS-RAF

186
Q

can have mutations in any stage/ pathway in cancer that either do what or what?

A

drive prolif
OR
prevent inactivation of these pathways

187
Q

RTKs and downstream pathways function to control what?

A

proliferation

188
Q

Apoptosis and cell death….

Apoptosis is not the only method for cell death, name another method?

A

necrosis

189
Q

cell death/ apoptosis is a critical part of the quiescence/diff + proliferation triangle.
what 2 things does it predict?

A

death signals OR absense of cell survival signals to induce cell death

190
Q

apoptosis is part of the normal developmental process, what benefit does it have to living organisms?

A

allows elimination of damaged cells
eg embryonic skin between digits

191
Q

what molecules mediate apoptosis?

A

caspases
also prevent transmission of damage -> daughter cells/ damage impinging on cellular function

192
Q

how do caspases break down cells?

A

cleave cellular proteins and cellular dna to break down cells

193
Q

outline the process by which caspases work to ultimately clear apoptotic bodies by macrophages via phagocytic clearance

A
  • condensation of nuceli + fragmentation of chrDNA
  • condensation + fragmentation of cytoplasm
  • organelles degraded
  • release of mitochondrial cytochrome C
  • membrane blebbing, apoptotic vesicle formation containing parts of degraded nucleus or organelles
    …
    = no inflammation
194
Q

apoptosis results in inflammation, true or false?

A

false

195
Q

in healthy cells what is apoptosis repressed by?

A

BCL2 - a protein family

196
Q

BCL2 and other proteins suppress apoptosis hence must be switched off for it to happen. List the main activation stimuli for apoptosis that fall under cellular stress?

A

DNA damage, loss of growth factors, anoxia and infection

197
Q

what are the 2 different types of apoptotic stimuli?

A

pro apoptotic receptors and cellular stress

198
Q

what are the 2 stages of apoptosis in mammals?

A
  1. de-repress repressors (BCL2)
  2. activate caspases
199
Q

de repressing BCL2 allows the activation of?

A

caspases: 9,7,3

200
Q

Cyto C is involved in formation of what?

A

apoptosome

201
Q

different forms of cellular stress induce apoptosis most commonly though what protein?

A

p53
integral part of response to DNA damage

202
Q

p53 is a transcription factor that induces apoptosis if dna cannot be repaired. What genes does it promote and what genes does it suppress?

A

promotes activation of pro apoptotic genes and suppresses anti apoptotic factors

203
Q

whats the master switch of apoptotic response?

A

p53

204
Q

p53 is the most highly mutated gene in human cancer and a tumour suppressor gene, true or false?

A

true

205
Q

how is p53 usually deregulated?

A

mutation

206
Q

what is the aim of most chemotherapies in relation to p53?

A

induce large levels of dna damage and cause p53 dependent apoptosis

207
Q

name a negative regulator of p53 that switches it off and degrades it?

A

MDM2

208
Q

what is the consequence of MDM2 over expression (trisomy of chr. 12) which is the case in a number of cancers?

A

loss of p53 activity

209
Q

name 3 different apoptosis pathways?

A

extrinsic, intrinsic and granzyme

210
Q

intrinsic apoptosis involves the release of what from the mitochondria?

A

cytochrome C

211
Q

what do BAX/BAK do in response to cellular stress?

A

form pores in the mitochondria leading to the release of cytochrome c

212
Q

release of cytochrome c leads to the activation of what 2 cellular proteins?

A

APAF1 and caspase 9

213
Q

APAF 1 and caspase 9 form a complex called apoptosome which activates caspase 9. what does this drive the activation of?

A

caspases 3, 6 and 7

214
Q

what 2 pro apoptotic genes drive the instrinsic apoptosis pathway?

A

BAX and BAK

215
Q

the extrinsic pathway of apoptosis is driven by signals such as FAS/ FAS-L/ FAS receptor, that activates what process?

A

mediator + execution of caspases 8 (mols that do degradation of cellular DNA + proteins)

216
Q

before apoptosis, the caspases 3,6 enter nucleus and what occurs?

A

DNA fragmentation and protein cleavage and degradation

217
Q

when do proapoptotic genes BAX and BAK activate and form pores in mitochondria?

A

when cells detect high levels of cellular stress

218
Q

are Bcl-2 and Bcl-xl examples of pro-survival members or pro-apoptotic members?

A

pro survival

219
Q

are Bax, Bak, Puma examples of pro-survival members or pro-apoptotic members?

A

pro apoptotic

220
Q

BCL2 is overexpressed in many tumours and drug resistant cell lines and deregulated by translocation of BCL2 gene. What effect does this have on apoptosis?

A

it drives BCL2 expression and suppresses apoptosis

221
Q

Targeted treatments…..

2 ways to target RTKs?

A
  1. target antibodies to receptor
  2. small mol inhibitors of RTK
222
Q

3 effects of targeting antibodies to receptor TK when using a targeting strategy?

A

inhibit ligand binding,
inhibit dimerization
induce killing of tumour cells

223
Q

what effect do small molecule inhibitors of RTK have?

A

block activity of receptor even if ligand is bound, prevent activation, switch off downstream signals and cell death

224
Q

why target RTKs?

A

to induce cell death and stop tumour cells growing

225
Q

whats the gold standard treatment of cancer?

A

targeting RTKs with antibodies

226
Q

how does Trastuzumab (herceptin) target HER2 ?

A

blocks internalisation and partial block of downstream signalling and promotes antibody dependent cytotox to kill tumour cells

227
Q

between trastuzumab and pertuzumab, which one blocks dimerization of HER2?

A

pertuzumab

228
Q

2 antibody drugs that may be used to treat HER-2 overexpression breast cancer?

A

trastuzumab and pertuzumab

229
Q

what effect does pertuzumab have on HER2?

A

blocks dimerization AND activation

completely switches off HER2

230
Q

out of trastuzumab and pertuzumab, which is effective in cancers where HER2 is activated but not over expressed hence applicable to other tumours too?

A

pertuzumab

231
Q

out of trastuzumab and pertuzumab, which is effective in cancers where HER2 is activated but not over expressed hence applicable to other tumours too?

A

pertuzumab

232
Q

EGFR is amplified in gliobastoma, breast and lung cancer. What effect do cetuxumab and panitumumab have on EGFR?

A

blocks EGF ligand binding, steric hinderance, promotes antibody dependent tox to kill cancer cells

233
Q

what is herceptin aka?

A

trastuzumab

234
Q

whihc drug inhibits internalisation/cleavage of HER.. Ab-dependant cell toxicity

A

trastuzumab, used in breast cancer

235
Q

lapantinib is a small molecule that targets EGFR and HER2, what is its moa?

A

reversible ATP competitor

236
Q

eg lapatinib binds HER2 and stops what conversion?

A

ATP -> ADP

237
Q

do patients with KRAS or WT KRAS mutations not respond to EGFR antibodies?

A

KRAS

238
Q

KRAS mutations are usually mutally exclusive with EGFR mutations, true or false?

A

true

239
Q

cetuximab inhibits ligand-dependent activation and is indicated in which cancers?

A

colorectal, colorectal with WT KRAS, heas and neck w radiotherapy

240
Q

Panatimumab inhibits ligand-dependent activation and is indicated in which cancers?

A

colorectal and colorectal with WT KRAS

241
Q

is cetuximab or panitumumab indicated in colorectal cancers PLUS head and neck?

A

cetuximab

242
Q

erlotinib is a small molecule developed against EGFR for lung and pancreatic cancer, what is its moa?

A

reversible atp competitor

243
Q

erlontinib/ geftinib response is defined by certained mutations, what does this mean?

A

some mutations prevent the binding of inhibitor so tumour regresses and small molecule cannot bind

244
Q

eventually tumours develop resistance against small molecules/antibodies at the site where they bind hence they must be combined with another or chemo, true or false?

A

true

245
Q

in lung cancer, resistance to what combo drugs: Thr790Met mutation prvenrts binding of inhibitor?

A

erlotinib and gefitinit

246
Q

what is gleevec (imantinib mesylate, novartis) a specific inhibitor for?

A

BCR-ABL tyrosine kinase

247
Q

what is the moa of gleevec (imantinib)?

A

competitive inhibitor of atp binding to active site, inhibits tyrosine kinase activity of BCR-ABL

248
Q

why is it important that second generation tyrosine kinase inhibitors have been developed in terms of resistance?

A

patients develop resistance to imantinib and relapse, point mutations within tyrosine kinase domain of BCR-ABL

249
Q

some px develop resistance to imatinib and relapse… tendency to relapse with resistant BCR-ABL mutants if treated in acute phase, called what?

A

blast crisis

250
Q

how are second gen tyr kinase inhibitors different to first gen?

A

can bind to mutated form and still have actvity

251
Q

what does vemurafenib inhibit?

A

BRAF

252
Q

we have inhibitors currently for only BRAF or WT BRAF?

A

BRAF (V600E mutation)

253
Q

drugs that target BCL2 and X inhibit tumour growth?

A

BCLXL

254
Q

name 2 inhibitor drugs that hit only BCL 2?

A

obatoclax and venetoclax

255
Q

name an inhibitor drug that works against both BCL2 and BCL XL?

A

navitoclax

256
Q

although navitoclax trials were promising, what were the setbacks?

A

toxic so patients developed thrombocytopenia

257
Q

a single dose of venetoclax results in tumor lysis within how many hrs?

A

24

258
Q

Tumour microenvironment + novel targets…..

are tumours homo or hetergeneous?

A

heterogeneous

259
Q

what is meant by TME?

A

all the host cells that surround the tumour which all interact together

260
Q

in the TME different cell types secrete different growth factors, cytokines and enzymes. what does this stimulate?

A

different host cells to interact with cancer cells

261
Q

name some cell types in TME?

A

CAF
EC
PC
CSC
CC
ICs
invasive cancer cell

262
Q

true or false, TME involves non maligant host cells?

A

true

263
Q

all immune cells are derived from what cell?

A

HSC
haematopoietic stem cell

264
Q

HSC cells split into what 2 branches?

A

myeloid and lymphoid progenitor cells

265
Q

which one of myeloid and lymphoid progenitor cells are innate, and which is adaptive IS?

A

myeloid: innate

lymphoid: adaptive

266
Q

the 4 cell types that come under myeloid progenitor cell?

A

innate IS

monocyte
basophil
neutrophil
eosinophil

267
Q

the 4 cell types that come under lymphoidprogenitor cell?

A

adaptive IS

T cell
B cell
NK cell
DC

268
Q

what 2 groups can t cells be divided into?

A

CD4 and 8

269
Q

what are the 2 types of immune tolerance mechanisms?

A

central and peripheral

270
Q

what is meant by central tolerance?
what happens to the B cells?

A

strongly self-reactive immature lymphocytes are deleted
Apoptosis of B cells in the bone marrow that recognize self-antigens

271
Q

what cells involved in central tolerance?

A

naive/premature I cells = thymocytes in thymus

272
Q

why is immune tolerance carrried out and how is it seen in autoimmune diseases?

A

body electing to remove I cells that strongly react to our own antigens to avoid self harm

273
Q

if immune cells bind too strongly to MHC I and II, what happens to them?

A

apoptosis

274
Q

what is meant by peripheral tolerance?

A

apoptosis of immune cells that recognise self antigens in the periphery and suppression of tregs

275
Q

outline what the immune surveillance theory is?

A

immune system constantly monitoring the body for the appearance of tumour cells and majority are destroyed before tumours manifest

276
Q

while immune surveillance is good and any genetic alterations/ transformation progression that leads to a tumour cell will be fixed and -> elimination, what 2 instances may occur to lead to survival of tumour cell?

A

resistant mechanisms (to immune surveillance)

or tolerance induction

277
Q

how does the immune system identify tumour cells?

A

in wild type with no mutations immune cells dont react as they identify this as self antigens, in mutations neoantigens are expressed by tumour cells so immune system able to recognise as foreign and trigger response

278
Q

immune cells are trained not to react against own small peptide/ protein called what?

A

antigen

279
Q

mutations in cancer genome -> expression of tumour associated ‘novel’ antigens called what?

A

neo-antigens

slightly altered normal proteins, so IS can recognise as foreign and trigger I response

280
Q

what sort of mutation may lead to neo-antigen formation?

A

nonsynonymous

281
Q

what is the carcinogenic processes (brief)

A

where lots of mutations are accumulated (diff types) that affect proteins that cells express making them diff to our own

282
Q

outline how t cells are activated and regulated?

A

signal 1: antigen presentation by antigen presenting cells via HLA (human MHC)

t cell receptor present in naive T cells binds to antigen triggering cell activation

signal 2: second costimulatorysignal to get fully activated

(MHCI/II on DC presented to tumour cell by binding to TCR)

283
Q

co stimulation is essential for t cell activation and is mediated by tightly controlled interplay of what types of molecules?

A

stimulatory and inhibitory receptor and ligand pairs

284
Q

inhib receptors + ligands expressed on T cells, APC, tumour cells been identified as targets for cancer immunotherapy why?

A

as theyre critical mediators of immune suppression in TME

285
Q

what is the role of cd28 in t cell activation?

A

it provides a critical co-stimulation (2nd) signal needed for t cell activation

286
Q

if you only had cd28 and their ligands what would happen to immune cell activation?

A

would be permanently activated
+ want to activate foreign antigen, solve invasion + go back to normal -> in this process, some costim factors etc come in eg CDLA4 + CD1

287
Q

imgine T cell in middle, what 2 types of cell will in interact with?

A

DC
tissue macrophage
tumour cell

288
Q

receptor ligand pairs of what CD have been termed as immune checkpoints?

A

CD28

289
Q

why is it a good idea to use immunotherapy to fight cancer?

A

immune cells have randomly generated TCRs that can recognise any neo antigen generated during carcinogenesis,

antigen specific t cells can remain long term after invading antigen has been eliminated (memory T),

the immune system can adapt to cancer heterogenity and mutability

290
Q

3 features that make immunotherapy a good cancer targeting strategy?

A

specificity, memory and adaptability

291
Q

once adaptive systemis activated, cells proliferate then differentiate into what 2 types of cells?

A

effector and memory

292
Q

memory cells stay quiescent but when are they used again?

A

when same antigen comes again, faster immune response triggered as have alr activated cells

293
Q

CTLA4 is a member of the CD28 family (co-regulatory receptors) and work as breaks to the immune system. where and how are they induced?

A

cell surface of t cells by antigen activation

294
Q

how does CTLA4 stop an immune reaction?

A

competes with CD28 ligands

on APCs

295
Q

whenever an immune cell is presented with an antigen is starts immune activation and the activation of CTLA4. Eventually numbers increase and it will outcompete it, why?

A

higher affinity to CD28 ligands

296
Q

the CTLA4 mechanism happens early or late in the immune response?

A

v early - works in immune priming stage of T cell activation

297
Q

whenever an immune cell is presented in an antigen, CD28 starts the immune activation and also sythesis of CTLA4 –>?

A

over expression of CTLA4 = compete w CD28 + eventually outcompete it as has higher affinity to CD28 ligands

298
Q

where is CTLA4 constitutively expressed?

A

on tregs

299
Q

what does CTLA4 on T cell do?

A

competes with CD28 ligands and stops/inhibits immune reaction @ priming phase of T cell activation

300
Q

CTLA4 negatively regulates co stimulation signalling and powefully reinforces once type of tolerance. Is this peripheral or central?

A

peripheral

301
Q

name a fully humanised monoclonal antibody which is an anti CTLA4 that prevents its binding with B7 ligands to prevent the progression of cancer?

A

ipilimumab

302
Q

patients on anti CTLA4 monocloncal antibodies such as ipilimumab can suffer immune related adverse effects (irAEs), list what some of these might be?

A

skin lesions, colitis, hepatitis and thyroiditis

303
Q

Risk of immune related adverse effects (irAEs) are not dose dependent, true or false?

A

false

304
Q

briefly explain the mechanism of CTLA4 function and inhibition?

A
  • APC and TCR bind
  • immune activation starts, activated t cell
  • CTLA4 activation
  • Eventually competes with CD28 ligands and stops t cell activation
  • when anti CTLA4 antibodies are given its receptors are blocked
  • this stops CTLA4 inhibition so immune cells can still work and react to neoantigens
305
Q

PD1 is an immune checkpoint, what is its inhibitory function mediated by?

A

tyrosine phosphate SHP2

306
Q

what is the role of tyrosine phosphate SHP2?

A

dephosphorylates signalling molecules downstream the TCR

307
Q

what are the 2 ligands of PD1?

A

PDL1 and PDL2

308
Q

what is the result of inflammation induced PDL1 expression in TME?

A

-> PD1 mediated T cell exhaustion, inhibiting anti tumour CD8 response

309
Q

why is the fact that PD1 a negative regulator of pre exisiting effector t cells relevant to cancer?

A

its blockade results in preferential stimulation of anti tumour t cells

310
Q

PD1 immune checkpoint works on already activated t cells, true or false?

A

true

311
Q

what superfamily does PD1 belong to? and what does it do?

A

immunoglobulin gene superfamily

involved in programmed cell death (PD)

312
Q

what pathway does tyrosine phosphatase SHP2 target?

A

TCR pathway

313
Q

how do tumour cells use PDL1 to protect themselves from attack?

A
  • tumour cells have IFN gamma receptor that recognises IFN gamma produced by T cells
  • this induces PDL1 expression
  • this reactive expression turns off T cells that are trying to attack the tumour
314
Q

how is PD-L1 expressed? 6 steps

A
  1. TCR binds to the antigen in the MHC
  2. binding induces IFN-y expression
  3. IFN-y recognition via cancer cell receptors
  4. IFN-y receptors signals to JAK1/2 receptors
  5. JAK 1/2 receptors induces PD-L1
  6. blocks activated T cells
315
Q

name some IMMUNE CHECKPOINTS?

A

activated T cell - PD1
naive T cells - CTLA4

316
Q

what discovery about PD1 ligation meant the inhibiting its engagement may improve immunity against infections/cancer?

A

that it induces T cells exhaustion

317
Q

what did anti-PDL1 treatment in tumour mice result in?

A

enhanced tumour specific T cell responses + inhibition of tumour growth

318
Q

pre clinical models demonstrate that PDL1 blockade increases the duration of DC-T cell interactions and promotes T cell activation in vivo.
what are 2 examples of anti-PDL1 antibody drugs?

A

pembrolizumab - melanoma
nivolumab

319
Q

MMRs tumours are more responsive to pembrolizumab or nivolumab?

A

pembrolizumab
thus been approved for any solid tumour with dMMR

319
Q

pembrolizumab + what therapy improved px survival of non small cell lung cancer NSCLC?

A

chemotherapy
as opposed to only chemo

320
Q

whats the correlation between PD-L1 and chance of response?

A

higher % of PDL1 ligand in tumours = higher chance of response
(as youre treating that)

321
Q

explain the MoA of PD1 function and inhibition in simple terms and 3 steps

A
  1. normal function: foreign antigen presented, stimulated APC, effector T cell binds PD1 to PDL1. causes…
  2. chronic PD-1 signalling in cancer. T cell not apoptotic but loses function = get exhausted T cell
  3. T cell expansion. when admin anti PD1/PDL1, stops exhaustion mechanism
    multiply, can keep anti tumour function and keep killing tumour cells
322
Q

Mechanism of CTLA4 function and inhibition
???? (extra card)

A

Blocking CTLA4 receptor stops CTLA4 inhibition, allowing immune cells to continue functioning and reacting to the antigens of tumour cells

323
Q

give an example of a combination of anti CTLA4 and anti PD1 therapy used in melanoma to increase response rate

A

nivolumab and ipiilimumab

324
Q

whats the difference between anti-CTLA4 and anti-PDL1 in terms of:
what they target?

A

anti CTLA4: CD28 pathway

anti PD1: TCR pathway

325
Q

is anti PD1 or anti CTLA4 the induced resistance mechanism (not hard wired/ present in all cells)?

A

antiPD1

326
Q

which out of antiCTLA4 or PD1 expands clonal diversity?

A

anti CTLA4

327
Q

which has rapid reposnes out of anti CTLA4 and PD1?

A

anti PD1

328
Q

whihc out of antiCTLA4 or PD1 can move T cells into cold tumours (those w v low immune cell popn infiltration)?

A

anti CTLA4

329
Q

is disease recurrence after response more frequent and significant in anti CTLA4 or anti PD1?

A

antiPD1

330
Q

Give examples of 3 FDA approved anti-PD1 drugs

A

nivolumab

pembrolizumab

cemiplimab

331
Q

Give an example of CTLA-4 drug? FDA approved

A

ipilimumab

332
Q

Give example of 3 FDA approved anti-PD L1 drugs?

A

atezolizumab

durvalumab

avelumab

333
Q

the response rates of diff tumour types to PD1/PDL1 checkpoint blockade tend to be proportional to what?

A

their corresponding tumour mutational burden (TMB)

… so higher TMB = more likely tumour will respond to PD1 or CTLA4. makes sense if tumour has higher mutations = has higher neoantigens thus is immunogenic = more likely to trigger immune response

334
Q

increased PDL1 expression been linked w immune response and currently used as a biomarker for what?

A

ICB therapy in NSCLC and urothelial carcinoma

335
Q

How can the mechanisms of resistance to immune checkpoint inhibitors (ICBs) be categorized?

A

primary

acquired

336
Q

primary resistance to ICB means px DO/DO NOT respond to ICB?

A

DO NOT

337
Q

acquired resistance to ICB can be intrinsic/ extrinsic. for intrinsic, cancer cells alter processes related to what? 4

A

immune recognition
cell signalling
gene expression
DNA damage response

338
Q

tumours w HIGHER/LOWER mutation burden are inherently more resistant (lower response)?

A

lower

339
Q

immunoediting suggests that constant interactions between immune system + cancer cells can = clone selection in tumour that lack expression of neoantigens thus resulting in what?

A

poor immunogenecity and resistacne to ICB

340
Q

high tumour intra-heterogeneity can increase likelihood of what?

A

that a poor immunogenic sub-clone is selected

341
Q

how can immune suppressive cells + inhib cytokines in TME cause resistance to ICB?
check 337 again

A

they can undermine anti tumour response (down regulate)
- Tregs, MDSCs tumour infiltration

342
Q

what do M2 macrophages do to -> resistance to ICB?
check 337 again

A

promote tumour progression

343
Q

VEGF levels higher in PD1 non-responding px.
is inhibition of VEGF linked w improved/ worse ICB response in renal carcinoma?

A

improved

344
Q

impaired priming of T cells trhough what process was associated w lack of TILs and ICB resistance in melanoma?

A

suppression off DC recruitment

345
Q

tumour mutations -> loss of HLA expression - what affect will this have on AP and immune response?

A

wont present antigen and wont trigger IR

346
Q

why do px who respond poorly to aPD1 therapy have lower response rate?

A

as they have less tumour associated memory T cells compared to responders

347
Q

some pathways intrinsic to cancer progression and initiation may also do what as a SE?

A

initiate immune/ ICB response

348
Q

hyper activation of MAPK signalling impairs TILs recruitment and function through what?

A

expression of VEGF and other inhib cytokines
… immune response

349
Q

PTEN deletion linked to decrease in cytotoxic T cell activity. what is loss of PTEN linked to?

A

resistance to aPD1

350
Q

usually loss of function of BRCA1 and 2 comes form what 2 things/ steps/

A
  1. inherited mutation in BRCA1 - usually 1 allele hereditary mutn
  2. second mutation arise as whole gene been deleted… loss of both alleles

usually happens @ onset/ during tumour development

351
Q

which DS break repair pathwya: HRR or NHEJ requires a homologous template?

A

HRR

352
Q

when can NHEJ occur?
what about HRR

A

any time other than mitosis

only in S/G2 of cell cycle

353
Q

a problem with HRR is losing genetic material- bases. why?

A

if have damage at ends of DNA strand, cell tries to cut off damage.. lose genetic material

354
Q

PARP has a role in most DNA repair pathways but mainly what?

A

repair of SS break = more common type of DNA damage but only involves damage to 1 of 2 strands

355
Q

PARP also inhibits NHEJ early stages. if suppress/ take away activity, what are cells now reliant on?

A

HR.
if cell not got functional BRCA1,2 = problem

356
Q

4 types of mechanisms of PARPi resistance?

A

BRCA related
DDR rewiring
pharmacological
drug target related

357
Q

toxic non homologous end joining NHEJ leads to what?

A

radial chromosome formation

358
Q

Which cancers are PARPis currently approved for treatment in?

A

Breast
Ovarian
Pancreatic

359
Q

2 main pathways of DNA double strand break repair

A

HR
NHEJ

360
Q

What do BRCA1,2 play an important role in? pathway

A

HR

361
Q

Rationale behind using PARPi in cancer therapy?

A

To induce damage that requires HR for repair

362
Q

In HR deficient cells treated with PARPi, what do you think might kill the cells?

A

The DSBs are repaired inappropriately by NHEJ (doesn’t care about where strands cut or got from) This gives rise to toxic chromosome fusions and kills the cells.

363
Q

What other cancers (or genetic backgrounds of cancers) do you think PARP inhibitors might be useful for?

A

BRCA1,2
…. Anything involved in HR and defecting the genes should,..?

364
Q

Tumours sometimes become resistant to PARP inhibitors. What can you imagine might be involved?

A

Restoration of HR by “re-mutation” of BRCA1/2
Losing NHEJ and BRCA1/2
Increased export of PARPi from the cell

Health 32 (11 decks)

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