1. Complementary activity of tyrosine kinase inhibitors against secondary kit mutations in imatinib-resistant gastrointestinal stromal tumours
- Author
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Suzanne George, Jonathan A. Fletcher, George D. Demetri, Chandrajit P. Raut, César Serrano, Channing Yu, Jeffrey T. Czaplinski, Meijun Zhu, Ajia Presnell, Grant Eilers, Julia Ketzer, Michael Heinrich, Sebastian Bauer, Adrián Mariño-Enríquez, Ewa Sicinska, Derrick Tao, Arin McKinley, Brian P. Rubin, Aristotle M. Mannan, Institut Català de la Salut, [Serrano C] Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, 20 Shattuck Street, Thorn 528, Boston, MA, USA. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Sarcoma Translational Research Laboratory, Vall d’Hebron Institute of Oncology, Barcelona, Spain. Servei d’Oncologia Mèdica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. [Mariño-Enríquez A, Tao DL, Eilers G, Zhu M] Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, 20 Shattuck Street, Thorn 528, Boston, MA, USA. [Ketzer J] Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany, Hospital Universitari Vall d'Hebron, and Vall d'Hebron Barcelona Hospital Campus
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Cancer Research ,Pyridines ,Medizin ,Other subheadings::Other subheadings::/drug therapy [Other subheadings] ,Imatinib resistant ,Medicaments antineoplàstics ,Mice ,0302 clinical medicine ,Neoplasms::Neoplasms by Site::Digestive System Neoplasms::Gastrointestinal Neoplasms [DISEASES] ,Sunitinib ,Gastrointestinal Neoplasms ,Sarcoma ,Gastrointestinal stromal tumours ,3. Good health ,Tracte gastrointestinal - Càncer ,Proto-Oncogene Proteins c-kit ,Oncology ,030220 oncology & carcinogenesis ,Imatinib Mesylate ,Female ,Tyrosine kinase ,medicine.medical_specialty ,Physiological Phenomena::Pharmacological and Toxicological Phenomena::Pharmacological Phenomena::Drug Resistance::Drug Resistance, Neoplasm [PHENOMENA AND PROCESSES] ,Gastrointestinal Stromal Tumors ,Otros calificadores::Otros calificadores::/farmacoterapia [Otros calificadores] ,Mice, Nude ,CHO Cells ,Predictive markers ,Article ,03 medical and health sciences ,Clinical Trials, Phase II as Topic ,Cricetulus ,neoplasias::neoplasias por localización::neoplasias del sistema digestivo::neoplasias gastrointestinales [ENFERMEDADES] ,medicine ,Animals ,Humans ,neoplasms ,Protein Kinase Inhibitors ,Resistència als medicaments ,fenómenos fisiológicos::fenómenos farmacológicos y toxicológicos::fenómenos farmacológicos::resistencia a medicamentos::resistencia a los antineoplásicos [FENÓMENOS Y PROCESOS] ,Competing interests ,business.industry ,Extramural ,Phenylurea Compounds ,Correction ,Xenograft Model Antitumor Assays ,digestive system diseases ,Drug Resistance, Neoplasm ,Family medicine ,Mutation ,business - Abstract
Predictive markers; Sarcoma; Gastrointestinal stromal tumours Marcadores predictivos; Sarcoma; Tumores del estroma gastrointestinal Marcadors predictius; Sarcoma; Tumors estromals gastrointestinals Background Most patients with KIT-mutant gastrointestinal stromal tumours (GISTs) benefit from imatinib, but treatment resistance results from outgrowth of heterogeneous subclones with KIT secondary mutations. Once resistance emerges, targeting KIT with tyrosine kinase inhibitors (TKIs) sunitinib and regorafenib provides clinical benefit, albeit of limited duration. Methods We systematically explored GIST resistance mechanisms to KIT-inhibitor TKIs that are either approved or under investigation in clinical trials: the studies draw upon GIST models and clinical trial correlative science. We subsequently modelled in vitro a rapid TKI alternation approach against subclonal heterogeneity. Results Each of the KIT-inhibitor TKIs targets effectively only a subset of KIT secondary mutations in GIST. Regorafenib and sunitinib have complementary activity in that regorafenib primarily inhibits imatinib-resistance mutations in the activation loop, whereas sunitinib inhibits imatinib-resistance mutations in the ATP-binding pocket. We find that rapid alternation of sunitinib and regorafenib suppresses growth of polyclonal imatinib-resistant GIST more effectively than either agent as monotherapy. Conclusions Our data highlight that heterogeneity of KIT secondary mutations is the main mechanism of tumour progression to KIT inhibitors in imatinib-resistant GIST patients. Therapeutic combinations of TKIs with complementary activity against resistant mutations may be useful to suppress growth of polyclonal imatinib-resistance in GIST. This work was supported in part by an ASCO Young Investigator Award (CS), a Spanish Society of Medical Oncology Translational Award (CS), Río Hortega-ISCIII CM14/00241 (CS) FERO Foundation (CS), US National Institutes of Health grants 1P50CA127003 (GDD, ES, JAF), 1P50CA168512 (JAF, AME), GIST Cancer Research Fund (JAF, MCH), Life Raft Group (JAF, MCH, SB), V Foundation Translational Grant (MCH), VA Merit Review Award (2I01BX000338–05) (MCH) and the Deutsche Krebshilfe (SB). CS acknowledges to the Cellex Foundation for providing facilities and equipment.
- Published
- 2019
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