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

Matthew S. Zabriskie, Christopher A. Eide, Srinivas K. Tantravahi, Nadeem A. Vellore, Johanna Estrada, Franck E. Nicolini, Hanna J. Khoury, Richard A. Larson, Marina Konopleva, Jorge E. Cortes, Hagop Kantarjian, Elias J. Jabbour, Steven M. Kornblau, Jeffrey H. Lipton, Delphine Rea, Leif Stenke, Gisela Barbany, Thoralf Lange, Juan Carlos Hernández-Boluda, Gert J. OssenkoppeleRichard D. Press, Charles Chuah, Stuart L. Goldberg, Meir Wetzler, Francois Xavier Mahon, Gabriel Etienne, Michele Baccarani, Simona Soverini, Gianantonio Rosti, Philippe Rousselot, Ran Friedman, Marie Deininger, Kimberly R. Reynolds, William L. Heaton, Anna M. Eiring, Anthony D. Pomicter, Jamshid S. Khorashad, Todd W. Kelley, Riccardo Baron, Brian J. Druker, Michael W. Deininger, Thomas O'Hare

Research output: Contribution to journalArticle

178 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)428-442
Number of pages15
JournalCancer Cell
Volume26
Issue number3
DOIs
StatePublished - 2014

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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    Zabriskie, M. S., Eide, C. A., Tantravahi, S. K., Vellore, N. A., Estrada, J., Nicolini, F. E., Khoury, H. J., Larson, R. A., Konopleva, M., Cortes, J. E., Kantarjian, H., Jabbour, E. J., Kornblau, S. M., Lipton, J. H., Rea, D., Stenke, L., Barbany, G., Lange, T., Hernández-Boluda, J. C., ... O'Hare, T. (2014). BCR-ABL1 Compound Mutations Combining Key Kinase Domain Positions Confer Clinical Resistance to Ponatinib in Ph Chromosome-Positive Leukemia. Cancer Cell, 26(3), 428-442. https://doi.org/10.1016/j.ccr.2014.07.006