CML Pharmacology

Question 1

BCR-ABL1 signaling mimics

Answer 1

growth factor activation

Question 2

imatinib blocks what

Answer 2

ATP binding site on BCR-ABL tyrosine kinase (STI571)

Question 3

CML is a rare example of what

Answer 3

single defect = disease

Question 4

Resistance to Imatinib

Answer 4

Altered metabolism (is CYP3A4 substrate). Beware grapefruit juice!!!
Altered membrance transport
Loss of p53 (which confers resistance to apoptosis)
Overexpresion of BCR-ABL1
Point mutations, especially of binding domain

Question 5

Nilotinib

Answer 5

induces deeper and faster remissions

similar side effect profile

Question 6

important long-term side effects of imatinib

Answer 6

muscle cramps, asthenia, edema, skin fragility, diarrhea, tendon/ligament abnormalities

Question 7

dasatinib

Answer 7

active against BCR-ABL1 and Src family
active against most point mutations (other than T315I)
Can cause fluid retention and pulmonary hypertension

Question 8

bosutinib

Answer 8

also active against BCR-ABL1 and Src family

Active against most point mutations (other than T315I)

Question 9

Ponitinib

Answer 9

Rationally designed based on crystal structure of T315I mutant
Is only agent active against this mutation
Causes clots and arterial fibrosis that can be fatal