BCR-ABL1 compound mutants display differential and dose-dependent responses to ponatinib
نویسندگان
چکیده
منابع مشابه
BCR-ABL1 compound mutations combining key kinase domain positions confer clinical resistance to ponatinib in Ph chromosome-positive leukemia.
Ponatinib is the only currently approved tyrosine kinase inhibitor (TKI) that suppresses all BCR-ABL1 single mutants in Philadelphia chromosome-positive (Ph(+)) leukemia, including the recalcitrant BCR-ABL1(T315I) mutant. However, emergence of compound mutations in a BCR-ABL1 allele may confer ponatinib resistance. We found that clinically reported BCR-ABL1 compound mutants center on 12 key pos...
متن کاملThe impact of multiple low-level BCR-ABL1 mutations on response to ponatinib.
The third-generation tyrosine kinase inhibitor (TKI) ponatinib shows activity against all common BCR-ABL1 single mutants, including the highly resistant BCR-ABL1-T315I mutant, improving outcome for patients with refractory chronic myeloid leukemia (CML). However, responses are variable, and causal baseline factors have not been well-studied. The type and number of low-level BCR-ABL1 mutations p...
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PURPOSE The Hedgehog signaling pathway is a key regulator of cell growth and differentiation during development. Whereas the Hedgehog pathway is inactive in most normal adult tissues, Hedgehog pathway reactivation has been implicated in the pathogenesis of several neoplasms including BCR-ABL1-positive leukemia. The clear link between the Hedgehog pathway and BCR-ABL1-positive leukemia led to an...
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Resistance to imatinib (Gleevec®) in cancer cells is frequently because of acquired point mutations in the kinase domain of BCR-ABL. Ponatinib, also known as AP24534, is an oral multi-targeted tyrosine kinase inhibitor (TKI), and it has been investigated in a pivotal phase 2 clinical trial. The histone deacetylase inhibitor vorinostat (suberoylanilide hydroxamic acid) has been evaluated for its...
متن کاملIKK-dependent activation of NF-κB contributes to myeloid and lymphoid leukemogenesis by BCR-ABL1.
The product of the Ph chromosome, the BCR-ABL1 tyrosine kinase activates diverse signaling pathways in leukemic cells from patients with chronic myeloid leukemia (CML) and Ph(+) B-cell acute lymphoblastic leukemia (B-ALL). Previous studies showed that nuclear factor κB (NF-κB) is activated in BCR-ABL1-expressing cells, but the mechanism of activation and importance of NF-κB to the pathogenesis ...
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ژورنال
عنوان ژورنال: Haematologica
سال: 2017
ISSN: 0390-6078,1592-8721
DOI: 10.3324/haematol.2017.176347