Exam 1 - Kinase Inhibitors

Question 1

___________ is the most common target of several kinases

Answer 1

tyrosine

Question 2

Type I kinase inhibitors bind the ________ conformation of kinases

Answer 2

active

Question 3

Type II kinase inhibitors bind and stabilize the _________ conformation of kinases

Answer 3

inactive

Question 4

Type III kinase inhibitors occupy an ______________ ________ outside of the ATP-binding pocket

Answer 4

allosteric pocket

Question 5

Which patients may show an enhanced response to EGFR inhibitors?

Answer 5

Patients with mutations in EGFR the cause the receptor to be constitutively activated

Question 6

Are gefitinib and erlotinib competitive or covalent inhibitors?

Answer 6

Competitive

Question 7

What are gefitinib and erlotinib approved for?

Answer 7

metastatic non-small cell lung cancer whose tumors have EGFR exon 19 or exon 21 mutations

Question 8

Afatinib is a _________ inhibitor of EGFR kinase activity, unlike gefitinib and erlotinib.

Answer 8

covalent

Question 9

What mutation causes resistance to gefitinib?

Answer 9

T790M

Question 10

Which EGFR inhibitor is effective against the T790M EGFR mutation?

Answer 10

Osimertinib

Question 11

Lapatinib is a reversible inhibitor of what two receptors?

Answer 11

EGFR and HER2

Question 12

What symptoms should you look out for while using lapatinib and why?

Answer 12

symptoms of CHF, because it can cause a (reversible) decrease in cardiac function

Question 13

Lapatinib and Tucatinib approved indication

Answer 13

advanced metastatic breast cancer in patients who have progressed on other therapies

(selective for HER2+ breast cancer)
(in combination with capecitabine and trastuzumab)
*Tucatinib has increased specificity for HER2

Question 14

What is the FLT3?

Answer 14

A cytokine receptor important for hematopoietic cell survival and proliferation

Question 15

What are two mutations found in FLT3? What do they lead to?

Answer 15

1. Internal tandem duplication (ITD) - more common
2. Activating mutation in TK domain - less common

These lead to increased proliferation and decreased apoptosis

Question 16

Which FLT3 inhibitors is specific for ITD mutations?

Answer 16

Quizartinib

Question 17

How does the Bcr-Abl chimeric protein lead to malignancy?

Answer 17

The kinase activity of the Bcr-Abl protein is constitutively active, which leads to malignancy

Question 18

What type of kinase inhibitor is Imatinib (Gleevec)? (Type I, II, or III)

Answer 18

Type II

Question 19

Imatinib (Gleevec) primary indication

Answer 19

Chronic myeloid leukemia

Question 20

Ponatinib is effective against all major resistant forms of BCR-Abl, most notably which one?

Answer 20

The “gatekeeper” mutation T315I that is resistant to all other BCR-Abl compounds