Direct Target : BCR/ABL1,KIT,PDGFRA,PDGFRB,CSF1R,DDR1
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 :
Nilotinib is an inhibitor of the BCR-ABL kinase. Nilotinib binds to and stabilizes the inactive conformation of the kinase domain of ABL protein. In vitro, nilotinib inhibited BCR-ABL mediated proliferation of murine leukemic cell lines and human cell lines derived from patients with Ph+ CML. Under the conditions of the assays, nilotinib was able to overcome imatinib resistance resulting from BCR-ABL kinase mutations, in 32 out of 33 mutations tested. In vivo, nilotinib reduced the tumor size in a murine BCR-ABL xenograft model.
Nilotinib inhibited the autophosphorylation of the following kinases at IC50 values as indicated: BCR-ABL (20 to 60 nM), PDGFR (69 nM), c-KIT (210 nM), CSF-1R (125 to 250 nM), and DDR1 (3.7 nM).
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. Nilotinib achieved a PFS of 57% and OS of 78% in a 48-month follow-up of a phase-II study (PMID: 22763385).
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.
