title: BCR-ABL1 compound mutations combining key kinase domain positions confer clinical resistance to ponatinib in Ph chromosome-positive leukemia.
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.
authors.affiliation: Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA.
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Zabriskie
authors.affiliation: 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.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Eide
authors.affiliation: 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.
authors.forename: Srinivas K
authors.initials: SK
authors.lastname: Tantravahi
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy and The Henry Eyring Center for Theoretical Chemistry, University of Utah, Salt Lake City, UT 84112, USA.
authors.forename: Nadeem A
authors.initials: NA
authors.lastname: Vellore
authors.affiliation: Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA.
authors.forename: Johanna
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authors.lastname: Estrada
authors.affiliation: Hematology Department 1F, Centre Hospitalier Lyon Sud, Pierre Bénite, INSERM U1052, CRCL, Lyon 69495, France.
authors.forename: Franck E
authors.initials: FE
authors.lastname: Nicolini
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA 30322, USA.
authors.forename: Hanna J
authors.initials: HJ
authors.lastname: Khoury
authors.affiliation: University of Chicago, Chicago, IL 60637, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Larson
authors.affiliation: Departments of Leukemia and Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Marina
authors.initials: M
authors.lastname: Konopleva
authors.affiliation: Departments of Leukemia and Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Jorge E
authors.initials: JE
authors.lastname: Cortes
authors.affiliation: Departments of Leukemia and Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Hagop
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authors.lastname: Kantarjian
authors.affiliation: Departments of Leukemia and Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
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authors.initials: EJ
authors.lastname: Jabbour
authors.affiliation: Departments of Leukemia and Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Kornblau
authors.affiliation: Department of Medical Oncology and Hematology, Allogeneic Blood and Marrow Transplantation Program, Princess Margaret Hospital, University of Toronto, Toronto ON M5G 2M9, Canada.
authors.forename: Jeffrey H
authors.initials: JH
authors.lastname: Lipton
authors.affiliation: Service des Maladies du Sang, Hospital Saint-Louis, 75010 Paris, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Rea
authors.affiliation: Department of Hematology, Karolinska Institutet and University Hospital, 17176 Stockholm, Sweden.
authors.forename: Leif
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authors.lastname: Stenke
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institutet, 17176 Stockholm, Sweden.
authors.forename: Gisela
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authors.lastname: Barbany
authors.affiliation: Hematology and Oncology, University of Leipzig, 04103 Leipzig, Germany.
authors.forename: Thoralf
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authors.lastname: Lange
authors.affiliation: Hematology and Medical Oncology Department, Hospital Clínico Universitario, 46010 Valencia, Spain.
authors.forename: Juan-Carlos
authors.initials: JC
authors.lastname: Hernández-Boluda
authors.affiliation: Department of Hematology, VU University Medical Center, Amsterdam 1081HV, the Netherlands.
authors.forename: Gert J
authors.initials: GJ
authors.lastname: Ossenkoppele
authors.affiliation: Department of Pathology and Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Press
authors.affiliation: Department of Hematology, Singapore General Hospital, Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, 169856 Singapore, Singapore.
authors.forename: Charles
authors.initials: C
authors.lastname: Chuah
authors.affiliation: John Theurer Cancer Center at Hackensack University Medical Center, Hackensack, NJ 07601, USA.
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authors.lastname: Goldberg
authors.affiliation: Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
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authors.affiliation: Laboratoire d'Hematologie, Centre Hospitalier Universitaire de Bordeaux and Laboratoire Hematopoïese Leucemique et Cible Therapeutique, Inserm U1035, Universite Bordeaux, 33076 Bordeaux, France.
authors.forename: Francois-Xavier
authors.initials: FX
authors.lastname: Mahon
authors.affiliation: Departement d'Oncologie Medicale, Centre Regional de Lutte Contre le Cancer de Bordeaux et du Sud-Ouest, Institut Bergonie, 33076 Bordeaux, France.
authors.forename: Gabriel
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authors.lastname: Etienne
authors.affiliation: Department of Experimental, Diagnostic, and Specialty Medicine, Institute of Hematology "L. e A. Seràgnoli," University of Bologna, 40138 Bologna, Italy.
authors.forename: Michele
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authors.lastname: Baccarani
authors.affiliation: Department of Experimental, Diagnostic, and Specialty Medicine, Institute of Hematology "L. e A. Seràgnoli," University of Bologna, 40138 Bologna, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Soverini
authors.affiliation: Department of Experimental, Diagnostic, and Specialty Medicine, Institute of Hematology "L. e A. Seràgnoli," University of Bologna, 40138 Bologna, Italy.
authors.forename: Gianantonio
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authors.lastname: Rosti
authors.affiliation: Service d'Hématologie et d'Oncologie, Université de Versailles, 75010 Paris, France.
authors.forename: Philippe
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authors.lastname: Rousselot
authors.affiliation: Department of Chemistry and Biomedical Sciences and Centre for Biomaterials Chemistry, Linnaeus University, 391 82 Kalmar, Sweden.
authors.forename: Ran
authors.initials: R
authors.lastname: Friedman
authors.affiliation: Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA.
authors.forename: Marie
authors.initials: M
authors.lastname: Deininger
authors.affiliation: Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA.
authors.forename: Kimberly R
authors.initials: KR
authors.lastname: Reynolds
authors.affiliation: Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA.
authors.forename: William L
authors.initials: WL
authors.lastname: Heaton
authors.affiliation: Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Eiring
authors.affiliation: Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA.
authors.forename: Anthony D
authors.initials: AD
authors.lastname: Pomicter
authors.affiliation: Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA.
authors.forename: Jamshid S
authors.initials: JS
authors.lastname: Khorashad
authors.affiliation: Department of Pathology, University of Utah, Salt Lake City, UT 84112, USA.
authors.forename: Todd W
authors.initials: TW
authors.lastname: Kelley
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy and The Henry Eyring Center for Theoretical Chemistry, University of Utah, Salt Lake City, UT 84112, USA.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Baron
authors.affiliation: 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.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Druker
authors.affiliation: 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.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Deininger
authors.affiliation: 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.
authors.forename: Thomas
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authors.lastname: O'Hare
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D020134:Catalytic Domain; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D016044:Fusion Proteins, bcr-abl / Q000737:chemistry / Q000235:genetics*; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000235:genetics*; D056004:Molecular Dynamics Simulation; D020125:Mutation, Missense; D010677:Philadelphia Chromosome; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D011724:Pyridazines / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D017211:Treatment Failure
chemical_list: D000970:Antineoplastic Agents; D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D011724:Pyridazines; C545373:ponatinib; D016044:Fusion Proteins, bcr-abl