ArticleCancer cell2014
BCR-ABL1 compound mutations combining key kinase domain positions confer clinical resistance to ponatinib in Ph chromosome-positive leukemia.
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Article in Cancer cell, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 188 papers, 1 of them a synthesis that pooled it.
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188citing papers in PubMed, 1 pooled it
22.8field-weighted citation impact, top 1% of its field
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Who cites it
188 citing papers in PubMed, 1 synthesis or guideline pooled it, 364 citations in OpenAlex.
- Clinical Insights into Structure, Regulation, and Targeting of ABL Kinases in Human Leukemia.International journal of molecular sciences · 2024Pooled it
- Olverembatinib (HQP1351), a well-tolerated and effective tyrosine kinase inhibitor for patients with T315I-mutated chronic myeloid leukemia: results of an open-label, multicenter phase 1/2 trial.Journal of hematology & oncology · 2022Trial
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- Ponatinib as first-line treatment for patients with chronic myeloid leukaemia in chronic phase: a phase 2 study.The Lancet. Haematology · 2015Trial
- A design approach for bitopic kinase inhibitors.Nature · 2026Article
- Intrinsic cellular resistance to BCR::ABL1 inhibitors.Haematologica · 2026Review
- Interleukin signaling mitigates the inhibitory effects of combined Src/BCR-ABL1 blockade on T-cell activity in Philadelphia chromosome-positive acute lymphoblastic leukemia.Haematologica · 2026Article
- Dual functional genomics reveals a broad and convergent landscape of asciminib resistance in BCR::ABL1.Genome medicine · 2026Article
- Reconsidering dualTranslational cancer research · 2026Article
- Inhibition of Pellino-1 reverts the progression and tyrosine kinase inhibitor resistance in chronic myeloid leukemia.Cell death & disease · 2026Article
- Molecularly targeted therapy and immunotherapy in leukemias.Journal of hematology & oncology · 2026Review
- A critical review of management of allogeneic transplant-eligible adults with Ph+ acute lymphoblastic leukaemia.British journal of haematology · 2026Review
- Ponatinib plus asciminib in myeloid blast-phase CML harboring a phasedFrontiers in oncology · 2026Article
- Innovative rapid screening for complex BCR-ABL1 kinase domain mutations in TKI-treated leukaemia patients.British journal of cancer · 2025Article
- Exploring the Allosteric Pathways of Asciminib in the Dual Inhibition of BCR-ABL1.Biomolecules · 2025Article
- Synergistic effect of asciminib with reduced doses of ponatinib in human Ph + myeloid leukemia with the T315M mutation.International journal of hematology · 2025Article
- The Inositol-5-Phosphatase SHIP1: Expression, Regulation and Role in Acute Lymphoblastic Leukemia.International journal of molecular sciences · 2025Review
128 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
42 authors at 19 institutions in 8 countries.
Matthew S ZabriskieHuntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA.
Christopher A EideDivision of Hematology and Medical Oncology, Oregon Health & Science University Knight Cancer Institute, Portland, OR 97239, USA; Howard Hughes Medical Institute, Portland, OR 97239, USA.
Srinivas K TantravahiHuntsman 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.
Nadeem A VelloreDepartment of Medicinal Chemistry, College of Pharmacy and The Henry Eyring Center for Theoretical Chemistry, University of Utah, Salt Lake City, UT 84112, USA.
Johanna EstradaHuntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA.
Franck E NicoliniHematology Department 1F, Centre Hospitalier Lyon Sud, Pierre Bénite, INSERM U1052, CRCL, Lyon 69495, France.
Hanna J KhouryDepartment of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA 30322, USA.
Richard A LarsonUniversity of Chicago, Chicago, IL 60637, USA.
Marina KonoplevaDepartments of Leukemia and Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Jorge E CortesDepartments of Leukemia and Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Hagop KantarjianDepartments of Leukemia and Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Elias J JabbourDepartments of Leukemia and Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Steven M KornblauDepartments of Leukemia and Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Jeffrey H LiptonDepartment of Medical Oncology and Hematology, Allogeneic Blood and Marrow Transplantation Program, Princess Margaret Hospital, University of Toronto, Toronto ON M5G 2M9, Canada.
Delphine ReaService des Maladies du Sang, Hospital Saint-Louis, 75010 Paris, France.
Leif StenkeDepartment of Hematology, Karolinska Institutet and University Hospital, 17176 Stockholm, Sweden.
Gisela BarbanyDepartment of Molecular Medicine and Surgery, Karolinska Institutet, 17176 Stockholm, Sweden.
Thoralf LangeHematology and Oncology, University of Leipzig, 04103 Leipzig, Germany.
Juan-Carlos Hernández-BoludaHematology and Medical Oncology Department, Hospital Clínico Universitario, 46010 Valencia, Spain.
Gert J OssenkoppeleDepartment of Hematology, VU University Medical Center, Amsterdam 1081HV, the Netherlands.
Richard D PressDepartment of Pathology and Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA.
Charles ChuahDepartment of Hematology, Singapore General Hospital, Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, 169856 Singapore, Singapore.
Stuart L GoldbergJohn Theurer Cancer Center at Hackensack University Medical Center, Hackensack, NJ 07601, USA.
Meir WetzlerRoswell Park Cancer Institute, Buffalo, NY 14263, USA.
Francois-Xavier MahonLaboratoire d'Hematologie, Centre Hospitalier Universitaire de Bordeaux and Laboratoire Hematopoïese Leucemique et Cible Therapeutique, Inserm U1035, Universite Bordeaux, 33076 Bordeaux, France.
Gabriel EtienneDepartement d'Oncologie Medicale, Centre Regional de Lutte Contre le Cancer de Bordeaux et du Sud-Ouest, Institut Bergonie, 33076 Bordeaux, France.
Michele BaccaraniDepartment of Experimental, Diagnostic, and Specialty Medicine, Institute of Hematology "L. e A. Seràgnoli," University of Bologna, 40138 Bologna, Italy.
Simona SoveriniDepartment of Experimental, Diagnostic, and Specialty Medicine, Institute of Hematology "L. e A. Seràgnoli," University of Bologna, 40138 Bologna, Italy.
Gianantonio RostiDepartment of Experimental, Diagnostic, and Specialty Medicine, Institute of Hematology "L. e A. Seràgnoli," University of Bologna, 40138 Bologna, Italy.
Philippe RousselotService d'Hématologie et d'Oncologie, Université de Versailles, 75010 Paris, France.
Ran FriedmanDepartment of Chemistry and Biomedical Sciences and Centre for Biomaterials Chemistry, Linnaeus University, 391 82 Kalmar, Sweden.
Marie DeiningerHuntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA.
Kimberly R ReynoldsHuntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA.
William L HeatonHuntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA.
Anna M EiringHuntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA.
Anthony D PomicterHuntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA.
Jamshid S KhorashadHuntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA.
Todd W KelleyDepartment of Pathology, University of Utah, Salt Lake City, UT 84112, USA.
Riccardo BaronDepartment of Medicinal Chemistry, College of Pharmacy and The Henry Eyring Center for Theoretical Chemistry, University of Utah, Salt Lake City, UT 84112, USA.
Brian J DrukerDivision of Hematology and Medical Oncology, Oregon Health & Science University Knight Cancer Institute, Portland, OR 97239, USA; Howard Hughes Medical Institute, Portland, OR 97239, USA.
Michael W DeiningerHuntsman 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.
Thomas O'HareHuntsman 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.
University of Utah · USHuntsman Cancer Institute · USThe University of Texas MD Anderson Cancer Center · USOregon Health & Science University · USUniversity of Bologna · ITKarolinska Institutet · SEAmsterdam UMC Location VUmc · NLCentre Hospitalier Universitaire de Bordeaux · FREmory University · USHackensack University Medical Center · USHôpital Saint-Louis · FRHospital Clínico Universitario de Valencia · ESInserm · FRInstitut Bergonié · FRLinnaeus University · SERoswell Park Comprehensive Cancer Center · USSingapore General Hospital · SGUniversity of Chicago · USUniversity of Toronto · CA
Funding
Tumor Evolution and Metastasis ProgramP30CA016672 · NCI · UNIVERSITY OF TX MD ANDERSON CAN CTR · PI Fabien Delerue · 1985 to 2026
$290.8MUTAH REGIONAL CANCER CENTERP30CA042014 · NCI · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · PI KATHARINE S ULLMAN · 1986 to 2026
$72.6MUnderstanding the origins of rapid recurrence of pancreatic cancer after resectionP30CA069533 · NCI · OREGON HEALTH & SCIENCE UNIVERSITY · PI Grace B Gill · 1997 to 2026
$60.5MTOLERANCE INDUCTION BY MEGADOSE STEM CELL TRANSPLANTS IN CML--GVHD AND GVLP01CA049639 · NCI · UNIVERSITY OF TX MD ANDERSON CAN CTR · PI SHPALL, ELIZABETH J · 1990 to 2014
$41.8MMechanisms of resistance to ponatinib therapy in chronic myeloid leukemiaR01CA178397 · NCI · UNIVERSITY OF UTAH · PI DEININGER, MICHAEL W., O'HARE, THOMAS J. · 2014 to 2018
$2.6MChronic Myelogenous Leukemia and BCR-ABL SubstratesR37CA065823 · NCI · OREGON HEALTH & SCIENCE UNIVERSITY · PI DRUKER, BRIAN J · 2011 to 2015
$1.5MBiology of Imatinib-Resistant Mutants of BCR-ABLR01HL082978 · NHLBI · OREGON HEALTH & SCIENCE UNIVERSITY · PI DEININGER, MICHAEL W. · 2005 to 2009
$1.5MHoward Hughes Medical InstituteNCI NIH HHS 5 P01 CA049639-23NCI NIH HHS P01 CA049639NCI NIH HHS P30 CA016672NCI NIH HHS P30 CA042014NCI NIH HHS P30 CA069533NCI NIH HHS R01 CA178397NCI NIH HHS R37 CA065823NCI NIH HHS R37CA065823NHLBI NIH HHS HL082978-01NHLBI NIH HHS R01 HL082978
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.
Indexed as
Antineoplastic AgentsCatalytic DomainDrug Resistance, NeoplasmFusion Proteins, bcr-ablHumansImidazolesLeukemia, Myelogenous, Chronic, BCR-ABL PositiveMolecular Dynamics SimulationMutation, MissensePhiladelphia ChromosomeProtein BindingProtein Kinase InhibitorsPyridazinesTreatment FailureAntineoplastic AgentsFusion Proteins, bcr-ablImidazolesponatinibProtein Kinase InhibitorsPyridazines
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