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Therapeutics IV > Cell Signaling in Cancer_Edit > Flashcards

Cell Signaling in Cancer_Edit Flashcards

1
Q

How many human kinases are there

A

518

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2
Q

The human kinases encode for how many genes

A

900

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3
Q

How many approved kinase inhibitors

A

66

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4
Q

First tyrosine kinase inhibitor

A

imatinib

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5
Q

3 most common driver mutations in lung cancer

A
  • unknown
  • KRAS
  • EGFR

(other smaller mutations: EML4-ALK, BRAF, PIK3CA, MET, ERBB2, MAP2K1, NRAS)

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6
Q

Major source of phosphate group that is going to be transferred by a kinase to a target protein

A

adenosine triphosphate (ATP)

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7
Q

Describe Type I Kinase Inhibitor

A

inhibitors bind to the active conformation of the kinase with the aspartate residue (white backbone) of the DFG motif pointing into the ATP-binding pocket.

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8
Q

Describe Type II Kinase Inhibitor

A

inhibitors bind and stabilize the inactive conformation of the kinase with the flipped aspartate residue facing outward of the binding pocket.

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9
Q

Describe Type III Kinase Inhibitor

A

inhibitors occupy an allosteric pocket outside of the ATP-binding pocket.

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10
Q

Describe Competitive Inhibitors

A

bind kinase in a reversible fashion and therefore must compete with ATP for binding.

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11
Q

Describe Covalent Inhibitors

A

tend to covalently bind with a reactive nucleophilic cysteine residue proximal to the ATP-binding site, resulting in the blockage of the ATP site and irreversible inhibition

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12
Q

Gefitinib is what type of inhibitor

A

Type 1 TKI

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13
Q

Gefitinib blocks

A

EGFR

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14
Q

Erlotinib blocks

A

EGFR

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15
Q

Gefitinib and Erlotinib approved for

A

the tx of metastatic non-small cell lung cancer (NSCLC) whose tumors have EGFR exon 19 or exon 21 (L858R) mutations

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16
Q

Afatinib blocks

A

ErbB (EGFR)

covalent inhibitor

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17
Q

Afatinib approved for

A

the tx of EGFR mutant non-small cell lung cancer (NSCLC) with EGFR mutations

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18
Q

Dacomitinib blocks

A

EGFR

covalent inhibitor

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19
Q

Dacomitinib approved for

A

non-resistant EGFR mutant lung cancer

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20
Q

Common EGFR Inhibitor SE

A

rash

associated with a good prognosis

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21
Q

What causes resistance to Geftinib

A

T790M

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22
Q

Osimertinib blocks

A

EGFR

third generation

covalent kinase inhibitor

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23
Q

Osimeritinib approved for

A

pts that acquire the T790M mutation

recent emergence of C797 mutations that abrogate covalent binding

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24
Q

Describe relationship between EGFR (ErbB1) and Her2 (ErbB2)

A

they can form a hetrodimer

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25
Q

When do you see Her2

A

amplified in breast cancer

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26
Q

Lapatinib is a

A

Her2 and EGFR inhibitor

reversible inhibitor of both EGFR and Her2

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27
Q

Lapatinib is selective for

A

the tx of Her2+ breast cancer

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28
Q

Lapatinib is currently approved with

A

Capecitabine for the tx of advanced metastatic breast cancer in pts who have progressed on other therapies

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29
Q

Neratinib blocks

A

EGFR

more favorable than gefitinib

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30
Q

Tucatinib is a

A

Her2 inhibitor

31
Q

Tucatinib is selective for the tx of

A

Her2+ breast cancer

32
Q

When use Tucatinib

A

SECOND line therapy (in COMBINATION with trastuzumab and capaceitabine) for the tx of advanced metastatic breast cancer in pts who have progressed on other therapies

33
Q

Capmatinib is a

A

MET inhibitor

34
Q

What is MET

A

receptor for hepatocyte growth factor (HGF)

35
Q

fibroblast growth factor receptor (FGFR) mutationally activated in

A

bladder cancer

36
Q

platelet derived growth factor receptor (PDGFR) mutationally activated in

A

gastrointestinal stromal tumors (GIST)

37
Q

rearranged during transfection (RET) becomes mutationally active in

A

NSCLC and thyroid cancer

38
Q

What is VEGFR?

A

Vascular Endothelial Growth Factor Receptor

critical to tumor angiogenesis

currently 7 FDA approved small molecules that inhibit VEGFR

39
Q

What is CML

A

chronic myelogenous leukemia

40
Q

What happens with CML and what is created

A

translocation occurs between chromosomes 9 and 22

the rearrangement of genomic material creates a fusion gene called Bcr-Abl that produces a protein (tyrosine kinase) that is thought to promote leukemia

41
Q

What drug blocks the activation of the Bcr-Abl protein

A

Imatinib (Gleevec)

42
Q

Describe the philadelphia chromosome (Ph1)

A

is the prototype chromosomal translocation

  • Formed by joining the 5’-portion of the Bcr gene (chromosome 22) with the 3’-portion of the Abl gene (chromosome 9)
  • A chimeric transcript is produced, called Bcr-Abl
  • Chimeric gene is transcribed into a novel 8.5 kb mRNA
  • RNA translated into a unique 210 kD protein not found in normal cells
43
Q

The Ph1 chromosome is demonstrable in

A

> 95% of CML

44
Q

Imatinib is a

A

Type II small molecule inhibitor of the Abl tyrosine kinase

45
Q

Inhibition of the Abl tyrosine kinase results in

A

both reduced proliferation and enhanced apoptotic cell death in CML and GIST

46
Q

Imatinib primary indication

A

tx of chronic myelocytic leukemia (CML)

47
Q

Ponatinib inhibits

A

Bcr-Abl

48
Q

Why is Ponatinib notable

A

It can inhibit the “gatekeeper” mutation T315I that is resistant to all other Bcr-Abl compounds

49
Q

Imatinib and Ponatinib bind Bcr-Abl in the

A

“DFG out” confirmation

50
Q

Acalabrutinib inhibits/blocks

A

BTK

also targets Cys481

covalent inhibitor

51
Q

Acalabrutinib indicated for

A

B-cell lymphoma (Mantle cell)

52
Q

What is a significant driver event in lung cancer

A

EML4-ALK translocation

53
Q

Describe ELM4-ALK translocation

A
  • Wild type ALK is a transmembrane receptor tyrosine kinase similar to EGFR.
  • When ALK becomes inappropriately fused to ELM4 (or other genes) it become cytoplasmic and constitutively active.
  • Occurs in 6% of non-small cell lung cancers
54
Q

Alectinib inhibits

A

ALK (anaplastic lymphoma kinase)

55
Q

Alectinib indicated for

A

the tx of patients with ALK+, metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib

56
Q

Brigatinib inhibits

A

ALK

57
Q

Brigatinib approved to treat

A

NSCLC that have ALK mutations

58
Q

Type of mutation with melanoma

A

BRAF mutation

59
Q

Dabrafenib blocks/inhibits

A

BRAF

second generation

60
Q

Dabrafenib approved for use

A

in combination with trametinib for the tx of BRAF V600E/K-mutant metastatic melanoma

activation of wild type BRAF remains a problem, combination with trametinib seems to stem induction of squamous cell carcinomas

61
Q

Trametinib blocks

A

MEK1 and MEK2

first approved Type III allosteric inhibitor

62
Q

Trametinib indicated

A

in combination with dabrafenib

63
Q

Trametinib NOT indicated for the tx of

A

pts who have received prior BRAF inhibitor therapy

64
Q

What is PI3K?

A

Phosphoinositide 3-kinase

lipid kinase that leads to downstream activation of protein kinase B (PKB/AKT) –> a pathway critical for cancer cell survival

toxicity is a major issue for these compounds

65
Q

Alpelisib is a

A

lipid kinase inhibitor in breast cancer

there are 4 isoforms of PI3K; the alpha isoform is mutationally activated in breast cancer

alpelisib is specific for the alpha isoform

66
Q

What mutations drive the indication for Alpelisib?

A

PIK3CA mutations

67
Q

Name 4 rapalogs

A
  1. Sirolimus
  2. Temsirolimus
  3. Everolimus
  4. Deforolimus
68
Q

Rapamycin is also known as

A

sirolimus

69
Q

Rapamycin analogues inhibit the function of

A

mTOR (mammalian target of rapamycin)

70
Q

mTOR is a

A

serine-threonine kinase

71
Q

What does rapamycin do?

A

inhibits immune response by blocking IL-2 signaling transduction

72
Q

Everolimus inhibits

A

mTORC1 and NOT mTORC2 which can lead to feedback activation of Akt

73
Q

Everolimus approved for

A

the tx of advanced renal carcinoma in pts who have failed sunitinib or sorafenib

74
Q

What is one of the goals of using rapamycin analogues

A

this “targeted” therapy is to decrease the use of toxic chemotherapies

targeting of one aspect/pathway involved in cell growth is not likely to produce a durable response

Therapeutics IV (19 decks)

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