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

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 - Jan 1 2014

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Leukemia
Phosphotransferases
Chromosomes
Mutation
Protein-Tyrosine Kinases
Philadelphia Chromosome
Molecular Dynamics Simulation
Alleles
ponatinib
Therapeutics

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

Cite this

Zabriskie, M. S., Eide, C. A., Tantravahi, S. K., Vellore, N. A., Estrada, J., Nicolini, F. E., ... 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

BCR-ABL1 Compound Mutations Combining Key Kinase Domain Positions Confer Clinical Resistance to Ponatinib in Ph Chromosome-Positive Leukemia. / Zabriskie, Matthew S.; Eide, Christopher A.; Tantravahi, Srinivas K.; Vellore, Nadeem A.; Estrada, Johanna; Nicolini, Franck E.; Khoury, Hanna J.; Larson, Richard A.; Konopleva, Marina; Cortes, Jorge E.; Kantarjian, Hagop; Jabbour, Elias J.; Kornblau, Steven M.; Lipton, Jeffrey H.; Rea, Delphine; Stenke, Leif; Barbany, Gisela; Lange, Thoralf; Hernández-Boluda, Juan Carlos; Ossenkoppele, Gert J.; Press, Richard D.; Chuah, Charles; Goldberg, Stuart L.; Wetzler, Meir; Mahon, Francois Xavier; Etienne, Gabriel; Baccarani, Michele; Soverini, Simona; Rosti, Gianantonio; Rousselot, Philippe; Friedman, Ran; Deininger, Marie; Reynolds, Kimberly R.; Heaton, William L.; Eiring, Anna M.; Pomicter, Anthony D.; Khorashad, Jamshid S.; Kelley, Todd W.; Baron, Riccardo; Druker, Brian J.; Deininger, Michael W.; O'Hare, Thomas.

In: Cancer Cell, Vol. 26, No. 3, 01.01.2014, p. 428-442.

Research output: Contribution to journalArticle

Zabriskie, MS, Eide, CA, Tantravahi, SK, Vellore, NA, Estrada, J, Nicolini, FE, Khoury, HJ, Larson, RA, Konopleva, M, Cortes, JE, Kantarjian, H, Jabbour, EJ, Kornblau, SM, Lipton, JH, Rea, D, Stenke, L, Barbany, G, Lange, T, Hernández-Boluda, JC, Ossenkoppele, GJ, Press, RD, Chuah, C, Goldberg, SL, Wetzler, M, Mahon, FX, Etienne, G, Baccarani, M, Soverini, S, Rosti, G, Rousselot, P, Friedman, R, Deininger, M, Reynolds, KR, Heaton, WL, Eiring, AM, Pomicter, AD, Khorashad, JS, Kelley, TW, Baron, R, Druker, BJ, Deininger, MW & 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, vol. 26, no. 3, pp. 428-442. https://doi.org/10.1016/j.ccr.2014.07.006
Zabriskie, Matthew S. ; Eide, Christopher A. ; Tantravahi, Srinivas K. ; Vellore, Nadeem A. ; Estrada, Johanna ; Nicolini, Franck E. ; Khoury, Hanna J. ; Larson, Richard A. ; Konopleva, Marina ; Cortes, Jorge E. ; Kantarjian, Hagop ; Jabbour, Elias J. ; Kornblau, Steven M. ; Lipton, Jeffrey H. ; Rea, Delphine ; Stenke, Leif ; Barbany, Gisela ; Lange, Thoralf ; Hernández-Boluda, Juan Carlos ; Ossenkoppele, Gert J. ; Press, Richard D. ; Chuah, Charles ; Goldberg, Stuart L. ; Wetzler, Meir ; Mahon, Francois Xavier ; Etienne, Gabriel ; Baccarani, Michele ; Soverini, Simona ; Rosti, Gianantonio ; Rousselot, Philippe ; Friedman, Ran ; Deininger, Marie ; Reynolds, Kimberly R. ; Heaton, William L. ; Eiring, Anna M. ; Pomicter, Anthony D. ; Khorashad, Jamshid S. ; Kelley, Todd W. ; Baron, Riccardo ; Druker, Brian J. ; Deininger, Michael W. ; O'Hare, Thomas. / BCR-ABL1 Compound Mutations Combining Key Kinase Domain Positions Confer Clinical Resistance to Ponatinib in Ph Chromosome-Positive Leukemia. In: Cancer Cell. 2014 ; Vol. 26, No. 3. pp. 428-442.
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AU - Vellore, Nadeem A.

AU - Estrada, Johanna

AU - Nicolini, Franck E.

AU - Khoury, Hanna J.

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AU - Hernández-Boluda, Juan Carlos

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AU - Wetzler, Meir

AU - Mahon, Francois Xavier

AU - Etienne, Gabriel

AU - Baccarani, Michele

AU - Soverini, Simona

AU - Rosti, Gianantonio

AU - Rousselot, Philippe

AU - Friedman, Ran

AU - Deininger, Marie

AU - Reynolds, Kimberly R.

AU - Heaton, William L.

AU - Eiring, Anna M.

AU - Pomicter, Anthony D.

AU - Khorashad, Jamshid S.

AU - Kelley, Todd W.

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