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

Cancer Cell

Summary

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. 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.

Graphical Abstract

 

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Highlights

 

  • BCR-ABL1 compound mutations can lead to clinical failures of ponatinib and other TKIs
  • Nearly all non-T315I compound mutants are sensitive to at least one approved TKI
  • T315I-inclusive compound mutants confer resistance to all TKIs, including ponatinib
  • Structural modeling provides a basis for design of TKIs targeting compound mutants

Ponatinib is the only currently approved tyrosine kinase inhibitor (TKI) that can inhibit all clinical BCR-ABL1 single mutations. Zabriskie et al. show that T315I-inclusive BCR-ABL1 compound mutants confer resistance to all clinical TKIs, including ponatinib, and provide structural explanations for the resistance.

Footnotes

1 Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA

2 Division of Hematology and Medical Oncology, Oregon Health & Science University Knight Cancer Institute, Portland, OR 97239, USA

3 Howard Hughes Medical Institute, Portland, OR 97239, USA

4 Division of Hematology and Hematologic Malignancies, University of Utah, Salt Lake City, UT 84112, USA

5 Department of Medicinal Chemistry, College of Pharmacy and The Henry Eyring Center for Theoretical Chemistry, University of Utah, Salt Lake City, UT 84112, USA

6 Hematology Department 1F, Centre Hospitalier Lyon Sud, Pierre Bénite, INSERM U1052, CRCL, Lyon 69495, France

7 Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA 30322, USA

8 University of Chicago, Chicago, IL 60637, USA

9 Departments of Leukemia and Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA

10 Department of Medical Oncology and Hematology, Allogeneic Blood and Marrow Transplantation Program, Princess Margaret Hospital, University of Toronto, Toronto ON M5G 2M9, Canada

11 Service des Maladies du Sang, Hospital Saint-Louis, 75010 Paris, France

12 Department of Hematology, Karolinska Institutet and University Hospital, 17176 Stockholm, Sweden

13 Department of Molecular Medicine and Surgery, Karolinska Institutet, 17176 Stockholm, Sweden

14 Hematology and Oncology, University of Leipzig, 04103 Leipzig, Germany

15 Hematology and Medical Oncology Department, Hospital Clínico Universitario, 46010 Valencia, Spain

16 Department of Hematology, VU University Medical Center, Amsterdam 1081HV, the Netherlands

17 Department of Pathology and Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA

18 Department of Hematology, Singapore General Hospital, Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, 169856 Singapore, Singapore

19 John Theurer Cancer Center at Hackensack University Medical Center, Hackensack, NJ 07601, USA

20 Roswell Park Cancer Institute, Buffalo, NY 14263, USA

21 Laboratoire d’Hematologie, Centre Hospitalier Universitaire de Bordeaux and Laboratoire Hematopoïese Leucemique et Cible Therapeutique, Inserm U1035, Universite Bordeaux, 33076 Bordeaux, France

22 Departement d’Oncologie Medicale, Centre Regional de Lutte Contre le Cancer de Bordeaux et du Sud-Ouest, Institut Bergonie, 33076 Bordeaux, France

23 Department of Experimental, Diagnostic, and Specialty Medicine, Institute of Hematology “L. e A. Seràgnoli,” University of Bologna, 40138 Bologna, Italy

24 Service d’Hématologie et d’Oncologie, Université de Versailles, 75010 Paris, France

25 Department of Chemistry and Biomedical Sciences and Centre for Biomaterials Chemistry, Linnaeus University, 391 82 Kalmar, Sweden

26 Department of Pathology, University of Utah, Salt Lake City, UT 84112, USA

Corresponding author

∗∗ Corresponding author

27 Co-first author

28 Co-senior author