Company : Bristol-Myers Squibb Company Inc
Direct Target : ABL1,SRC families((SRC,LCK,YES,FYN),KIT,EPHA2,PDGFRB
Drug Type : Multi-target inhibitor
Indications : In NCCN Guidelines, point mutations in the BCR-ABL1 kinase domain are a frequent mechanism of secondary resistance to first-line TKI therapy (like imatinib) and are associated with poor prognosis and higher risk of disease progression. E255K/V, F359C/V, Y253H, and T315I mutants are most commonly associated with disease progression and relapse. Dasatinib, nilotinib, and bosutinib are the second-line therapies for imatinib-resistant BCR-ABL1 kinase domain mutants (except T315I). Ponatinib and asciminib are active against most of the resistant BCR-ABL1 kinase domain mutants including T315I.
Specifically, bosutinib and dasatinib have demonstrated activity in patients with BCR-ABL1 mutants resistant to nilotinib (Y253H, E255K/V, and F359C/I/V). Bosutinib has minimal activity against F317L mutation (which is resistant to dasatinib) and nilotinib may be preferred over bosutinib in patients with F317L mutation. Ponatinib is active against BCR-ABL1 mutants resistant to dasatinib or nilotinib, including E255V, Y253H, and F359V, in addition to T315I. The contraindicated mutations for each therapy are as following: T315I confers complete resistance to imatinib, dasatinib, nilotinib, and bosutinib. The T315A, F317L/I/V/C, and V299L mutants are resistant to dasatinib and E255K/V, F359V/C, and Y253H mutants are resistant to nilotinib. G250E, and V299L mutants are resistant to bosutinib.
Mechanism Of Action :
Dasatinib, at nanomolar concentrations, inhibits the following kinases: BCR-ABL, SRC family (SRC, LCK, YES, FYN), c-KIT, EPHA2, and PDGFRβ. Based on modeling studies, dasatinib is predicted to bind to multiple conformations of the ABL kinase. In vitro, dasatinib was active in leukemic cell lines representing variants of imatinib mesylate sensitive and resistant disease. Dasatinib inhibited the growth of chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL) cell lines overexpressing BCR-ABL. Under the conditions of the assays, dasatinib was able to overcome imatinib resistance resulting from BCR-ABL kinase domain mutations,activation of alternate signaling pathways involving the SRC family kinases (LYN, HCK), and multi-drug resistance gene overexpression.
Efficacy & Safety : Dasatinib, nilotinib, and bosutinib are more potent than imatinib in vitro and retain activity against many of the imatinib-resistant BCR-ABL1 kinase domain mutants except T315I. Dasatinib achieved a PFS of 42% and OS of 65% in a 7-year follow-up of phase-III study NCT00123474 (PMID: 27192969). The incidence of drug-related pleural effusion was acceptable (28%-35%) and drug-related pulmonary hypertension and pulmonary arterial hypertension remained low (≤3%) (PMID: 27192969).
Reference Source : Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Guideline Name V.3.2022.◎ National Comprehensive Cancer Network, Inc. 2022. All rights reserved. Accessed [Jan. 27, 2022]. To view the most recent and complete version of the guideline, go online to NCCN.org.
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