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

Question 1

How many human kinases are there?

Answer 1

518

Question 2

How many genes encoding potential kinases have been identified?

Answer 2

900

Question 3

What are kinases?

Answer 3

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

Question 4

How many currently approved kinase inhibitors?

Answer 4

66

Question 5

What was the first approved kinase inhibitor?

Answer 5

Imatinib

Question 6

What do kinase inhibitors require to guide their application?

Answer 6

biomarkers

Question 7

How are mutations identified for kinase inhibitors?

Answer 7

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

Question 8

Describe diagnostic molecular pathology

Answer 8

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

Question 9

How is cell signaling driven?

Answer 9

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

Question 10

What is a common target of several kinases?

Answer 10

Tyrosine

Question 11

What can also be phosphorylated?

Answer 11

serine and threonine and lipids

Question 12

What balances the activity of kinases by removing phosphates?

Answer 12

phosphatases

Question 13

Which are better understood? Kinases or phosphatases?

Answer 13

Kinases.

Kinases are prime targets for small molecule inhibitors

Question 14

What does the general structure of a kinase entail?

Answer 14

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

Question 15

How many types of kinase inhibitors are there?

Answer 15

3

Question 16

Describe a type I kinase inhibitor

Answer 16

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

Question 17

Describe a type II kinase inhibitor

Answer 17

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

Question 18

Describe a type III kinase inhibitor

Answer 18

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

Question 19

Describe competitive inhibitors

Answer 19

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

Question 20

Describe covalent inhibitors

Answer 20

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)

Question 21

3 potential amino acid targets of phosphorylation

Answer 21

• serine
• threonine
• tyrosine

Question 22

EGFR is activated in _________ cancer

Answer 22

lung

Question 23

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

Answer 23

constitutively; enhanced

Question 24

Afatinib and neratinib are __________ inhibitors

Answer 24

covalent

Question 25

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

Answer 25

Gefitinib

Question 26

Gefitinib brand

Answer 26

Iressa

Question 27

Epidermal growth factor receptor (EGFR) functions through __________

Answer 27

tyrosine kinase activity

Question 28

EGFR signaling induces ___ ______________

Answer 28

cell proliferation

Question 29

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

Answer 29

overexpressed and has higher signaling activity

Question 30

EGFR overexpression correlates with ______ prognosis

Answer 30

poor

Question 31

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

Answer 31

reversible; EGFR; competitively; kinase

Question 32

Inhibition of kinase activity turns _____ signal to proliferate

Answer 32

off

Question 33

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

Answer 33

exon 19; exon 21 (L858R)

Question 34

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

Answer 34

...fatigue, rash, diarrhea

Question 35

Afatinib brand

Answer 35

Gilotrif

Question 36

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

Answer 36

covalent

Question 37

What is afatinib approved for?

Answer 37

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

Question 38

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

Answer 38

Dacomitinib

Question 39

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

Answer 39

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

Question 40

What causes resistance to Geftinib?

Answer 40

T790

Question 41

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

Answer 41

key; "lock"; T790M

Question 42

What are the two third generation EGFR inhibitors?

Answer 42

Gefitinib and Osimertinib

Question 43

The Abl protein is a __________

Answer 43

tyrosine kinase

Question 44

Imatinib brand

Answer 44

Gleevec

Question 45

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

Answer 45

II

Question 46

Constitutive activity results in ____________

Answer 46

malignancy

Question 47

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

Answer 47

proliferation; apoptotic cell death; CML; GIST

Question 48

Primary indication for Imatinib

Answer 48

Treatment of chronic myelocytic leukemia (CML)

Question 49

Toxicities of Imatinib

Answer 49

- nausea and vomiting - fluid retention and edema - neutropenia and thrombocytopenia frequent but mild

Question 50

Ponatinib is a _________ inhibitor

Answer 50

BCR-Abl

Question 51

Ponatinib is effective against all the major forms of __________

Answer 51

BCR-Abl

Question 52

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

Answer 52

inhibit; T315I; "DFG out"

Question 53

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

Answer 53

second; covalent BTK; Cys481; selective

Question 54

Acalabrutinib is indicated for...

Answer 54

...B-cell lymphoma (Mantle cell)

Question 55

What is a significant driver event in lung cancer?

Answer 55

EML4-ALK

Question 56

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

Answer 56

- Unknown (36.4%) - KRAS (25%) - EGFR (23%)

Question 57

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

Answer 57

transmembrane

Question 58

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

Answer 58

cytoplasmic; constitutively; 6%

Question 59

Alectinib brand

Answer 59

Alecensa

Question 60

Alectinib is a _____ ________ inhibitor of ALK

Answer 60

more specific

Question 61

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

Answer 61

anaplastic lymphoma kinase (ALK); diagnostic

Question 62

When is Alectinib indicated for treatment?

Answer 62

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

Question 63

_________ also recently approved NSCLC that have ALK mutations

Answer 63

Brigatinib

Question 64

Dabrafenib brand

Answer 64

tafinlar

Question 65

Dabrafenib is a second generation _________ inhibitor

Answer 65

BRAF-V600

Question 66

Dabrafenib indication

Answer 66

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

Question 67

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

Answer 67

Ras; BRAF-V600; Dabrafenib

Question 68

Trametinib brand

Answer 68

Mekinist

Question 69

Trametinib inhibits the kinase activity of _____ and _____

Answer 69

MEK1; MEK2

Question 70

Trametinib was recently approved to be used in combination with...

Answer 70

...Dabrafenib

Question 71

What is the first approved type III allosteric inhibitor

Answer 71

Trametinib

Question 72

What is Trametinib's limitation of use

Answer 72

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

Question 73

Most common adverse reactions for Trametinib

Answer 73

- rash - diarrhea - lymphedema

Question 74

____ 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.

Answer 74

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

Question 75

What is the first example of an isospecific compound

Answer 75

Alpelisib

Question 76

Alpelisib brand

Answer 76

Piqray

Question 77

How many isoforms of PI3K

Answer 77

4

Question 78

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

Answer 78

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

Question 79

What drives the indication for Alpelisib

Answer 79

PIK3CA mutations

Question 80

Name 4 rapalogs

Answer 80

- sirolimus - temsirolimus - everolimus - deforolimus

Question 81

What do rapamycin analogues do?

Answer 81

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

Question 82

What is rapamycin also known as

Answer 82

sirolimus

Question 83

mTOR is a ______-______ kinase

Answer 83

serine-threonine

Question 84

rapamycin analogues inhibit the immune response by blocking ________

Answer 84

IL-2 signaling transduction

Question 85

Everolimus brand

Answer 85

Afinitor

Question 86

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

Answer 86

oncology; immunosupressive effects

Question 87

Everolimus is currently approved for...

Answer 87

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

Question 88

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

Answer 88

mTORC1; mTORC2; Akt

Question 89

_________ remains a major issue

Answer 89

resistance

Question 90

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.

Answer 90

toxic chemotherapies; durable