| Literature DB >> 25132497 |
Matthew S Zabriskie1, Christopher A Eide2, Srinivas K Tantravahi3, Nadeem A Vellore4, Johanna Estrada1, Franck E Nicolini5, Hanna J Khoury6, Richard A Larson7, Marina Konopleva8, Jorge E Cortes8, Hagop Kantarjian8, Elias J Jabbour8, Steven M Kornblau8, Jeffrey H Lipton9, Delphine Rea10, Leif Stenke11, Gisela Barbany12, Thoralf Lange13, Juan-Carlos Hernández-Boluda14, Gert J Ossenkoppele15, Richard D Press16, Charles Chuah17, Stuart L Goldberg18, Meir Wetzler19, Francois-Xavier Mahon20, Gabriel Etienne21, Michele Baccarani22, Simona Soverini22, Gianantonio Rosti22, Philippe Rousselot23, Ran Friedman24, Marie Deininger1, Kimberly R Reynolds1, William L Heaton1, Anna M Eiring1, Anthony D Pomicter1, Jamshid S Khorashad1, Todd W Kelley25, Riccardo Baron4, Brian J Druker2, Michael W Deininger26, Thomas O'Hare27.
Abstract
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 positions and confer varying resistance to imatinib, nilotinib, dasatinib, ponatinib, rebastinib, and bosutinib. T315I-inclusive compound mutants confer high-level resistance to TKIs, including ponatinib. In vitro resistance profiling was predictive of treatment outcomes in Ph(+) leukemia patients. Structural explanations for compound mutation-based resistance were obtained through molecular dynamics simulations. Our findings demonstrate that BCR-ABL1 compound mutants confer different levels of TKI resistance, necessitating rational treatment selection to optimize clinical outcome.Entities:
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Year: 2014 PMID： 25132497 PMCID： PMC4160372 DOI： 10.1016/j.ccr.2014.07.006
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743