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Cancer Cell. 2014 Sep 8;26(3):428-442. doi: 10.1016/j.ccr.2014.07.006. Epub 2014 Aug 14.

BCR-ABL1 compound mutations combining key kinase domain positions confer clinical resistance to ponatinib in Ph chromosome-positive leukemia.

Author information

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; Howard Hughes Medical Institute, Portland, OR 97239, USA.
3
Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA; Division of Hematology and Hematologic Malignancies, University of Utah, Salt Lake City, UT 84112, USA.
4
Department of Medicinal Chemistry, College of Pharmacy and The Henry Eyring Center for Theoretical Chemistry, University of Utah, Salt Lake City, UT 84112, USA.
5
Hematology Department 1F, Centre Hospitalier Lyon Sud, Pierre Bénite, INSERM U1052, CRCL, Lyon 69495, France.
6
Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA 30322, USA.
7
University of Chicago, Chicago, IL 60637, USA.
8
Departments of Leukemia and Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
9
Department of Medical Oncology and Hematology, Allogeneic Blood and Marrow Transplantation Program, Princess Margaret Hospital, University of Toronto, Toronto ON M5G 2M9, Canada.
10
Service des Maladies du Sang, Hospital Saint-Louis, 75010 Paris, France.
11
Department of Hematology, Karolinska Institutet and University Hospital, 17176 Stockholm, Sweden.
12
Department of Molecular Medicine and Surgery, Karolinska Institutet, 17176 Stockholm, Sweden.
13
Hematology and Oncology, University of Leipzig, 04103 Leipzig, Germany.
14
Hematology and Medical Oncology Department, Hospital Clínico Universitario, 46010 Valencia, Spain.
15
Department of Hematology, VU University Medical Center, Amsterdam 1081HV, the Netherlands.
16
Department of Pathology and Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA.
17
Department of Hematology, Singapore General Hospital, Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, 169856 Singapore, Singapore.
18
John Theurer Cancer Center at Hackensack University Medical Center, Hackensack, NJ 07601, USA.
19
Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
20
Laboratoire d'Hematologie, Centre Hospitalier Universitaire de Bordeaux and Laboratoire Hematopoïese Leucemique et Cible Therapeutique, Inserm U1035, Universite Bordeaux, 33076 Bordeaux, France.
21
Departement d'Oncologie Medicale, Centre Regional de Lutte Contre le Cancer de Bordeaux et du Sud-Ouest, Institut Bergonie, 33076 Bordeaux, France.
22
Department of Experimental, Diagnostic, and Specialty Medicine, Institute of Hematology "L. e A. Seràgnoli," University of Bologna, 40138 Bologna, Italy.
23
Service d'Hématologie et d'Oncologie, Université de Versailles, 75010 Paris, France.
24
Department of Chemistry and Biomedical Sciences and Centre for Biomaterials Chemistry, Linnaeus University, 391 82 Kalmar, Sweden.
25
Department of Pathology, University of Utah, Salt Lake City, UT 84112, USA.
26
Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA; Division of Hematology and Hematologic Malignancies, University of Utah, Salt Lake City, UT 84112, USA. Electronic address: michael.deininger@hci.utah.edu.
27
Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA; Division of Hematology and Hematologic Malignancies, University of Utah, Salt Lake City, UT 84112, USA. Electronic address: thomas.ohare@hci.utah.edu.

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.

PMID:
25132497
PMCID:
PMC4160372
DOI:
10.1016/j.ccr.2014.07.006
[Indexed for MEDLINE]
Free PMC Article

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