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 Ossenkoppele; Richard 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

doi: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

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

Authors

Matthew S Zabriskie¹, Christopher A Eide², Srinivas K Tantravahi³, Nadeem A Vellore⁴, Johanna Estrada¹, Franck E Nicolini⁵, Hanna J Khoury⁶, Richard A Larson⁷, Marina Konopleva⁸, Jorge E Cortes⁸, Hagop Kantarjian⁸, Elias J Jabbour⁸, Steven M Kornblau⁸, Jeffrey H Lipton⁹, Delphine Rea¹⁰, Leif Stenke¹¹, Gisela Barbany¹², Thoralf Lange¹³, Juan-Carlos Hernández-Boluda¹⁴, Gert J Ossenkoppele¹⁵, Richard D Press¹⁶, Charles Chuah¹⁷, Stuart L Goldberg¹⁸, Meir Wetzler¹⁹, Francois-Xavier Mahon²⁰, Gabriel Etienne²¹, Michele Baccarani²², Simona Soverini²², Gianantonio Rosti²², Philippe Rousselot²³, Ran Friedman²⁴, Marie Deininger¹, Kimberly R Reynolds¹, William L Heaton¹, Anna M Eiring¹, Anthony D Pomicter¹, Jamshid S Khorashad¹, Todd W Kelley²⁵, Riccardo Baron⁴, Brian J Druker², Michael W Deininger²⁶, Thomas O'Hare²⁷

Affiliations

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Antineoplastic Agents / therapeutic use
Catalytic Domain
Drug Resistance, Neoplasm / genetics*
Fusion Proteins, bcr-abl / chemistry
Fusion Proteins, bcr-abl / genetics*
Humans
Imidazoles / chemistry
Imidazoles / pharmacology*
Imidazoles / therapeutic use
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics*
Molecular Dynamics Simulation
Mutation, Missense
Philadelphia Chromosome
Protein Binding
Protein Kinase Inhibitors / pharmacology
Protein Kinase Inhibitors / therapeutic use
Pyridazines / chemistry
Pyridazines / pharmacology*
Pyridazines / therapeutic use
Treatment Failure

Substances

Antineoplastic Agents
Imidazoles
Protein Kinase Inhibitors
Pyridazines
ponatinib
Fusion Proteins, bcr-abl

Abstract

Publication types

MeSH terms

Substances

Grants and funding