BCR-ABL1 Compound Mutations Combining Key Kinase Domain Positions Confer Clinical Resistance to Ponatinib in Ph Chromosome-Positive Leukemia

• Type of Material: Article
• Authors: Matthew S. Zabriskie, University of Utah; Christopher A. Eide, Oregon Health and Science University; Srinivas K. Tantravahi, University of Utah; Nadeem A. Vellore, University of Utah; Johanna Estrada, University of Utah; Franck E. Nicolini, Centre Hospitalier Lyon Sud; Hanna Khoury, Emory University; Richard A. Larson, University of Chicago; Marina Konopleva, University of Texas MD Anderson Cancer Center; Jorge E. Cortes, University of Texas MD Anderson Cancer Center; Hagop Kantarjian, University of Texas MD Anderson Cancer Center; Elias J. Jabbour, University of Texas MD Anderson Cancer Center; Steven M. Kornblau, University of Texas MD Anderson Cancer Center; Jeffrey H. Lipton, University of Toronto; Delphine Rea, Hopital Saint-Louis; Leif Stenke, Karolinska Institutet; Gisela Barbany, Karolinska Institutet; Thoralf Lange, University of Leipzig; Juan-Carlos Hernandez-Boluda, Hospital Clínico Universitario; Gert J. Ossenkoppele, Vrije Universiteit Amsterdam
• Language: English
• Date: 2014-09-08
• Publisher: Elsevier (Cell Press): 12 month embargo
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2014 Elsevier Inc.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.ccr.2014.07.006
• Title of Journal or Parent Work: Cancer Cell
• ISSN: 1535-6108
• Volume: 26
• Issue: 3
• Start Page: 428
• End Page: 442
• Grant/Funding Information: H.J.K. thanks the Georgia Cancer Coalition for a tissue bank-supporting grant.; This work was supported by Howard Hughes Medical Institute and NIH/NCI MERIT award R37CA065823 (B.J.D.).; T.O. is supported by the NIH/NCI (R01 CA178397).; A.M.E. is currently a Fellow of the Leukemia & Lymphoma Society (5090-12).; M.W.D. is supported by the NIH (HL082978-01, 5 P01 CA049639-23 and R01 CA178397), was a Leukemia & Lymphoma Society (LLS) Scholar in Clinical Research (7036-01), and is an investigator on LLS SCOR7005-11.; S.K.T is a recipient of 2013 Research Training Award for Fellows from the American Society of Hematology.; We acknowledge support in conjunction with grant P30 CA042014 awarded to the Huntsman Cancer Institute (T.O.).; R.B. acknowledges funding from the University of Utah Department of Medicinal Chemistry, a computing allocation at the XSEDE supercomputers (award TG-CHE120086) and the Director's Discretionary Program (Epigenetics), which used resources of ALCF, supported by the Office of Science of the U.S. Department of Energy (DE-AC02-06CH11357).
• Keywords: Science & Technology; THERAPY; Cell Biology; CONTROL INHIBITOR DCC-2036; Oncology; CHRONIC MYELOID-LEUKEMIA; T315I MUTANT; IMATINIB-MESYLATE; BCR-ABL MUTATIONS; Life Sciences & Biomedicine; CHRONIC PHASE; TYROSINE KINASE; NILOTINIB; DASATINIB BMS-354825
• Research Categories: Health Sciences, Oncology

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-ABL1T315I 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. Invitro 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.