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Therapeutics > Exam 1 lecture 3 > Flashcards

Exam 1 lecture 3 Flashcards

1
Q

What is unique about the action of tamoxifen as compared to fluvestrant

A

It activates ER in bone

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2
Q

Which of the following is not a hormone responsive cancer type? Prostate, ovarian, breast, endometrial

A

Ovarian

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3
Q

which of the following drugs is only used in post menopausal setting
Letrozole, tamoxifen, leuprolide, raloxifene`

A

Letrozole

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4
Q

Which cpd acts directly on AR.
Leuprolide, Abiraterone, Degarelix, enzalutamide

A

enzalutamide

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5
Q

How do we identify types of mutations and predict drug response?

A

We take a biopsy and the molecular signature will be what we use to prescribe the medication

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6
Q

How are genomic DNA from lung cancer biopsies tested? what is it looking for?

A

via PCR to look for a specific mutation in EGFR. If positive undergo anti egfr therapy

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7
Q

Cell signaling is largely driven by the transfer of

A

Phosphates

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8
Q

WHat is a major source of phosphate that is transferred by kinase to protein

A

ATP

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9
Q

What are common targets of kinases for phosphorylation

A

Tyrosine is a common target of several kinases. Serine, threonine and lipids can also be phosphorylated.

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10
Q

What removes phosphates in kinases

A

Phosphatases

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11
Q

What are the three types of kinase inhibitors

A

Type 1- bind to active conformation of kinase
Type 2- Bind and stabilize inactive conformation of kinases
Type 3- occupy allosteric pocket outside of ATP binding pocket

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12
Q

difference between competitive inhibitors and covalent inhibitors

A

competitive inhibitors bind kinase in a reversible fashion and therefore must compete with ATP for binding.
Covalent inhibitors tend to covalently bind with a reactive nucleophile cysteine residue proximal to the ATP binding site, resulting in blockage of ATP side and irreversible inhibition

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13
Q

Which aa is not a target of phosphorylation. Tyrosine, serine, threonine, alanine

A

Alanine

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14
Q

Name drugs that inhibit EGFR

A

Gefetinib
Osmertinib
Afatinib
Lapatinib

Tucatinib is preferentially a HER2 inhibitor

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15
Q

What happens when there is a mutation present in EGFR

A

mutations in EGFR cause receptor to be constitutively active

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16
Q

EGFR signalling induces ______

A

cell proliferation

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17
Q

EGFR is overexpressed in what percent of human cancers?

A

25-50%

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18
Q

EGFR overexpression is correlated with

A

Poor prognosis

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19
Q

What is erlotinib

A

A small molecule inhibitor of EGFR tyrosine kinase

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20
Q

How does erlotinib work?

A

competitively inhibits enzyme by binding to the ATP binding site. Inhibition of kinase activity turns off signal to proliferate

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21
Q

What are gefatinib and erlotinib approved for?

A

Treatment of patients with NSCLC whose tumors have L858R mutations

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22
Q

MOA of afatinib? What does it treat?

A

MOA- Covalent inhibitor of all ERB receptors. It is approved for treatment of EGFR mutant NSCLC

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23
Q

What causes resistance to gefitinib?

A

T790M mutation

24
Q

What is a drug that works in the presence of T790M mutation?

A

Osimertinib

25
Q

What happens to HER2 in breast cancer

A

It is genomically amplified

26
Q

What does lapatinib treat? MOA?

A

MOA- small molecule tyrosine kinase inhibitor that blocks HER2 and EGFR signaling reversibly

selective for tx of HER2 (+) breast cancer

27
Q

SIde effects of lapatinib

A

Diarrhea, nausea and vomiting. Reversible decline in cardiac function

28
Q

MOA of tucatinib? What is it selective for? What is it currently approved for?

A

MOA- small molecule tyrosine kinase inhibitor that preferentially binds HER2.
Selective for treatment of HER2+ breast cancer

approved for 2nd line therapy for tx of advanced breast cancer (along with capecitabine and trastumazab)

29
Q

adverse reactions of tucatinib and lapatinib compare

A

Tucatinib adverse reactions appear to be reduced compared to lapatinib due to increased specificity of HER2

30
Q

Which cpds inhibit EGFR?

A

Gefitinib, osmertinib, afatinib, lapatinib

31
Q

What mutation in EGFR confers resistance to 1st and 2nd generation
EGFR inhibitors

A

T790M

32
Q

acronyms for AML, FLT3,

What is the correlation between the two

A

AML- acute myeloid leukemia

FLT3- FMS- like tyrosine kinase

FLT3 mutations are found in 30% of acute myeloid leukemias

33
Q

What is FLT3 and what do its mutations cause?

A

FLT3 ligand is a cytokine receptor important for hematopoietic cell survival and cell proliferation.

Mutations lead to increased proliferation and reduced apoptosis

34
Q

Differentiate between 1st gen FLT3 inhibitors, 2nd gen and Type II inhibitors

A

1st gen- Midostaurin, broad kinase inhibitors

2nd gen- crenolanib, are more specific

Type II inhibitors- quizartinib, are specific for ITD mutations.

35
Q

What is the philadelphia chromosome (PH1)? How is it formed? How common is it in myeloid leukemia?

A

the philadelphia chromosome is a prototype chromosomal translocation

it is formed by joining 5’ portion of Bcr gene with 3’ portion of abl gene. Bcr-abl formed.

The philadelphia chromosome is demonstrable in 95% of chronic myeloid leukemia

36
Q

Use of Bcr-abl

A

Bcr-abl drived several proliferation pathways

37
Q

What type of drug is Imatinib (MOA)? Primary indication of Imatinib? toxicities?

A

Imatinib is a type II small molecule inhibitor of the abl tyrosine kinase.

Inhibition of Abl tyrosine kinase results in reduced proliferation and enhanced apoptotic cell death in CML and GIST

Primary indication is chronic myeloid leukemia

toxicities- N/v, fluid retention and edema

38
Q

How long do patients need to be on abl inhibitors?

A

life long

39
Q

Ponatinib MOA? What is a notable thing about ponatinib?

A

Ponatinib is a BCR-abl inhibitor. It can inhibit the gatekeeper mutation T315i that is resistant to all BCR-abl inhibitors.

effective against all major forms of BCR-ABL mytations.

40
Q

What is ALK?

A

wild type ALK is a transmembrane receptor tyrosine kinase similar to EGFR.

41
Q

What happens when ALK fuses with ELM? What does this lead to?

A

When ALK beocmes inappropriately fused to ELM-4 it becomes cytoplasmic and constituitively active.

This occurs in 6% of non small cell lung cancers

42
Q

what type of drug is alectinib (MOA)? What does it treat?

A

Inhibits the tyrosine kinase ALK.

It is indicated for the treatment of patients with anaplastic lymphoma kinase (ALK) positive NSCLC who are intolerant to crizotinib

43
Q

What other drug is approved from NSCLC drugs that have ALK mutations other than alectinib?

A

brigatinib

44
Q

BRAF place in cancer?

A

In melanoma, there is a specific mutation in BRAF

45
Q

What type of drug is Dabrafenib? (MOA)

What is it approved to treat? What responds to Dabrafenib? What does not?

A

Dabrafenib is a 2nd gen BRAF-V600 inhibitor

Approved for treatemnt of BRAF V600 metastatic melanoma and NSCLC patients that test positive for BRAF V600

Colorectal cancer with RAS and BRAF V600 mutations do not respond to Dabrafenib

46
Q

MOA of trametinib? Limitation of use? Adverse effect?

A

Trametinib inhibits the kinase activity of MEK 1 and MEK 2. First approved type III allosteric inhibitor.

Limitation of use- MEKINIST is not indicated for the treatment of patients who have received prior BRAF inhibitor therapy

most common adverse effect- rash

47
Q

What is BTK? What is it important for?

A

BTK (burtons tyrosine kinase) is important for normal B cells activity and B cell tumor growth.

48
Q

Name a covalent inhibitor of BTK

A

ibrutinib

49
Q

What does BTK treat?

A

Used primarily in mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL)

50
Q

What type of drug is acalabrutinib? (MOA) Compare it to ibrutinib?
WHat does it treat?

A

Acalabrutinib is a 2nd gen covalent BTK inhibitor. It targets Cys 481.

It is more potent and selective than 1st gen ibrutinib.

Indicated for B cell lymphoma (MCL and CLL)

51
Q

What are the rapamycin analogues also known as? What do they inhibit?

A

Rapamycin is also known as sirolimus.

Rapamycin inhibits function of mammalian target of rapamycin (mTOR)

52
Q

What type of kinase is mTOR

A

mTOR is a serine threonine kinase

53
Q

how does rapamycin inhibit immune response?

A

Blocks IL-2 signaling transduction

54
Q

Everolimus MOA

A

only inhibits mTORC1 and not mTORC2 which can lead to feedback activation of Akt

55
Q

What is the use of everolimus?

A

used in advanced renal carcinoma and also as an immunosuppressive after an organ transplant

56
Q

Which of the following drugs targets Her2?
a) Sirolimus
b) Alectinib
c) Vemurafinib
d) Tucatinib

A

tucatinib

57
Q
A

Therapeutics (15 decks)

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