Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

Therapeutics IV > Cell Signaling in cancer, targeting inhibition of kinase activity - Dr. Wendt > Flashcards

Cell Signaling in cancer, targeting inhibition of kinase activity - Dr. Wendt Flashcards

1
Q

How many human kinases are there?

A

518

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

How many genes encoding potential kinases have been identified?

A

900

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

What are kinases?

A

One of the largest classes of proteins encoded by the human genome

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

How many currently approved kinase inhibitors?

A

66

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

What was the first approved kinase inhibitor?

A

Imatinib

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

What do kinase inhibitors require to guide their application?

A

biomarkers

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

How are mutations identified for kinase inhibitors?

A

From tumor biopsy and data that is used as predictors of drug response

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

Describe diagnostic molecular pathology

A

Genomic DNA from lung cancer biopsies are tested via PCR for a particular mutation of EGFR. If positive, these patients will go on anti-EGFR therapies

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

How is cell signaling driven?

A

Driven by the transfer of phosphates. Adenosine triphosphate (ATP) is the major source of the phosphate group that is going to be transferred by a kinase to a target protein

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

What is a common target of several kinases?

A

Tyrosine

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

What can also be phosphorylated?

A

serine and threonine and lipids

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

What balances the activity of kinases by removing phosphates?

A

phosphatases

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

Which are better understood? Kinases or phosphatases?

A

Kinases.

Kinases are prime targets for small molecule inhibitors

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

What does the general structure of a kinase entail?

A

Generally made up of N- and C- lobes connected by a hinge region. An activation loop containing a Asp-Phe-Gly (DFG) motif control access to the active site

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

How many types of kinase inhibitors are there?

A

3

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

Describe a type I kinase inhibitor

A

Type I 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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

Describe a type II kinase inhibitor

A

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

***Can also engage in an active conformation

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

Describe a type III kinase inhibitor

A

Type III inhibitors occupy an allosteric pocket outside of the ATP-binding pocket

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

Describe competitive inhibitors

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
20
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 (often need to be much more specific)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
21
Q

3 potential amino acid targets of phosphorylation

A
  • serine
  • threonine
  • tyrosine
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
22
Q

EGFR is activated in _________ cancer

A

lung

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
23
Q

Mutations in EGFR cause the receptor to be ___________ activated. Patients with these mutations show an ___________ response to EGFF inhibitors

A

constitutively; enhanced

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
24
Q

Afatinib and neratinib are __________ inhibitors

A

covalent

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
25
Q

Which EGFR inhibitor was pulled (2005) and then reapproved (2015) for use?

A

Gefitinib

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
26
Q

Gefitinib brand

A

Iressa

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
27
Q

Epidermal growth factor receptor (EGFR) functions through __________

A

tyrosine kinase activity

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
28
Q

EGFR signaling induces ___ ______________

A

cell proliferation

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
29
Q

In 25 - 50% of human cancers, EGFR is _______________

A

overexpressed and has higher signaling activity

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
30
Q

EGFR overexpression correlates with ______ prognosis

A

poor

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
31
Q

Erlotinib is a small molecule __________ inhibitor of the _______ tyrosine kinase. It _____________ inhibits the enzyme by binding to the ATP binding site in the _________ domain

A

reversible; EGFR; competitively; kinase

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
32
Q

Inhibition of kinase activity turns _____ signal to proliferate

A

off

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
33
Q

Gefitinib and Erlotinib are approved for treatment of patients with metastatic non-small cell lung cancer (NSCLC) who tumors have EGFR ________ or _________ mutations

A

exon 19; exon 21 (L858R)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
34
Q

Gefitinib and Erlotinib are well tolerated. Most adverse effects are…

A

…fatigue, rash, diarrhea

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
35
Q

Afatinib brand

A

Gilotrif

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
36
Q

Afatinib is replacing older compounds and is a ___________ inhibitor of all ErbB receptors

A

covalent

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
37
Q

What is afatinib approved for?

A

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

38
Q

What is another covalent inhibitor approved for non-resistant EGFR mutant lung cancer?

A

Dacomitinib

39
Q

SE associated with EGFR inhibitors. It can be a good thing

A

rash. Not sure why/how this happens, but it indicates the disease is more stable

40
Q

What causes resistance to Geftinib?

A

T790

41
Q

Osimertinib is essentially a new ____ to fit the change in _____ that occurs upon acquisition of the _____ mutation

A

key; “lock”; T790M

42
Q

What are the two third generation EGFR inhibitors?

A

Gefitinib and Osimertinib

43
Q

The Abl protein is a __________

A

tyrosine kinase

44
Q

Imatinib brand

A

Gleevec

45
Q

Gleevec is a type ___ small molecule inhibitor of the Abl tyrosine kinase

A

II

46
Q

Constitutive activity results in ____________

A

malignancy

47
Q

Inhibition of the Abl tyrosine kinase results in both reduced __________ and enhanced ___________ in ____ and ____

A

proliferation; apoptotic cell death; CML; GIST

48
Q

Primary indication for Imatinib

A

Treatment of chronic myelocytic leukemia (CML)

49
Q

Toxicities of Imatinib

A
  • nausea and vomiting
  • fluid retention and edema
  • neutropenia and thrombocytopenia frequent but mild
50
Q

Ponatinib is a _________ inhibitor

A

BCR-Abl

51
Q

Ponatinib is effective against all the major forms of __________

A

BCR-Abl

52
Q

Notably, ponatinib can __________ the “gatekeeper” mutation ________ that is resistant to all other BCR-Abl compounds. All these compounds bind BCR-Abl in the _________ confirmation

A

inhibit; T315I; “DFG out”

53
Q

Acalabrutinib is a _______ generation ________ inhibitor that similarly targets _______. It is more potent and more __________ than 1st generation

A

second; covalent BTK; Cys481; selective

54
Q

Acalabrutinib is indicated for…

A

…B-cell lymphoma (Mantle cell)

55
Q

What is a significant driver event in lung cancer?

A

EML4-ALK

56
Q

What are the three biggest distributions of driver mutations in lung cancer?

A
  • Unknown (36.4%)
  • KRAS (25%)
  • EGFR (23%)
57
Q

Wild type ALK is a _________ receptor tyrosine kinase similar to EGFR

A

transmembrane

58
Q

When ALK becomes inappropriately fused to ELM4 (or other genes) it becomes ___________ and ________ active. It occurs in ___ of non-small cell lung cancers

A

cytoplasmic; constitutively; 6%

59
Q

Alectinib brand

A

Alecensa

60
Q

Alectinib is a _____ ________ inhibitor of ALK

A

more specific

61
Q

Alectinib inhibits tyrosine kinase called ________________. It requires a companion ________ test for the fusion gene

A

anaplastic lymphoma kinase (ALK); diagnostic

62
Q

When is Alectinib indicated for treatment?

A

Indicated for the treatment of patients with anaplastic lymphoma kinase (ALK)- positive, metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib. This indication is approved under accelerated approval based on tumor response rate and duration of response

63
Q

_________ also recently approved NSCLC that have ALK mutations

A

Brigatinib

64
Q

Dabrafenib brand

A

tafinlar

65
Q

Dabrafenib is a second generation _________ inhibitor

A

BRAF-V600

66
Q

Dabrafenib indication

A

for use in combination with trametinib for treatment 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. Also approved for the NSCLC patients that test positive for BRAF-600 mutations

67
Q

Colorectal cancer commonly has ___ and _____ mutations but these tumors do not respond to __________

A

Ras; BRAF-V600; Dabrafenib

68
Q

Trametinib brand

A

Mekinist

69
Q

Trametinib inhibits the kinase activity of _____ and _____

A

MEK1; MEK2

70
Q

Trametinib was recently approved to be used in combination with…

A

…Dabrafenib

71
Q

What is the first approved type III allosteric inhibitor

A

Trametinib

72
Q

What is Trametinib’s limitation of use

A

Its not indicated for the treatment of patients who have received prior BRAF inhibitor therapy

73
Q

Most common adverse reactions for Trametinib

A
  • rash
  • diarrhea
  • lymphedema
74
Q

____ is a lipid kinase that leads to the downstream activation of __________. This pathway is critical for cancer cell survival. Toxicity is a major issue with several of these compounds.

A

Phosphoinositide 3-kinase (PI3K); protein kinase B (PKB/AKT)

75
Q

What is the first example of an isospecific compound

A

Alpelisib

76
Q

Alpelisib brand

A

Piqray

77
Q

How many isoforms of PI3K

A

4

78
Q

What is the isoform of PI3K that is mutually activated in breast cancer?

A

alpha isoform. This cuts down on the toxicity seen from other PI3K inhibitors

79
Q

What drives the indication for Alpelisib

A

PIK3CA mutations

80
Q

Name 4 rapalogs

A
  • sirolimus
  • temsirolimus
  • everolimus
  • deforolimus
81
Q

What do rapamycin analogues do?

A

These compounds inhibit the function of mammalian target of Rapamycin (mTOR). Originally developed as an antifungal but failed in this capacity and was pursued as an anticancer agent

82
Q

What is rapamycin also known as

A

sirolimus

83
Q

mTOR is a ______-______ kinase

A

serine-threonine

84
Q

rapamycin analogues inhibit the immune response by blocking ________

A

IL-2 signaling transduction

85
Q

Everolimus brand

A

Afinitor

86
Q

In addition to oncology, Everolimus is also used in ____________ due to its ____________

A

oncology; immunosupressive effects

87
Q

Everolimus is currently approved for…

A

…treatment of advanced renal carcinoma, in patients who have failed sunitinib or sorafenib

88
Q

Everolimus only inhibits ________ and not ________ which can lead to feedback activation of ______

A

mTORC1; mTORC2; Akt

89
Q

_________ remains a major issue

A

resistance

90
Q

One of the goals of these “targeted” therapies is to decrease the use of ______ ___________. Targeting of one aspect/pathway involved in cell growth is not likely to produce a ________ response. Improved diagnoses will drive a continuing diagnosis in cancer.

A

toxic chemotherapies; durable

Therapeutics IV (19 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions