J Cho1, S Y Kim1, Y J Kim2,3, M H Sim1, S T Kim1, N K D Kim3, K Kim1, W Park3, J H Kim4, K-T Jang5, J Lee6. 1. Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 06351, Korea. 2. Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, Korea. 3. Samsung Genome Institute, Samsung Medical Center, Seoul, Korea. 4. Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. 5. Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. 6. Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 06351, Korea. jyunlee@skku.edu.
Abstract
PURPOSE: The KIT inhibitor, imatinib, has shown promising efficacy in patients with KIT-mutated melanoma; however, acquisition of resistance to imatinib occurs rapidly in the majority of patients. The mechanisms of acquired resistance to imatinib in melanoma remain unclear. METHODS: We analyzed biopsy samples from paired baseline and post-treatment tumor lesions in one patient with KIT-mutated melanoma who had had an initial objective tumor regression in response to imatinib treatment followed by disease progression 8 months later. RESULTS: Targeted deep sequencing from post-treatment biopsy samples detected an additional mutation in CTNNB1 (S33C) with original KIT L576P mutation. We examined the functional role of the additional CTNNB1 S33C mutation in resistance to imatinib indirectly using the Ba/F3 cell model. Ba/F3 cell lines transfected with both the L576P KIT mutation and the CTNNB1 S33C mutation demonstrated no growth inhibition despite imatinib treatment, whereas growth inhibition was observed in the Ba/F3 cell line transfected with the L576 KIT mutation alone. CONCLUSIONS: We report the first identification of the emergence of a CTNNB1 mutation that can confer acquired resistance to imatinib. Further investigation into the causes of acquired resistance to imatinib will be essential to improve the prognosis for patients with KIT-mutated melanoma.
PURPOSE: The KIT inhibitor, imatinib, has shown promising efficacy in patients with KIT-mutated melanoma; however, acquisition of resistance to imatinib occurs rapidly in the majority of patients. The mechanisms of acquired resistance to imatinib in melanoma remain unclear. METHODS: We analyzed biopsy samples from paired baseline and post-treatment tumor lesions in one patient with KIT-mutated melanoma who had had an initial objective tumor regression in response to imatinib treatment followed by disease progression 8 months later. RESULTS: Targeted deep sequencing from post-treatment biopsy samples detected an additional mutation in CTNNB1 (S33C) with original KITL576P mutation. We examined the functional role of the additional CTNNB1S33C mutation in resistance to imatinib indirectly using the Ba/F3 cell model. Ba/F3 cell lines transfected with both the L576PKIT mutation and the CTNNB1S33C mutation demonstrated no growth inhibition despite imatinib treatment, whereas growth inhibition was observed in the Ba/F3 cell line transfected with the L576 KIT mutation alone. CONCLUSIONS: We report the first identification of the emergence of a CTNNB1 mutation that can confer acquired resistance to imatinib. Further investigation into the causes of acquired resistance to imatinib will be essential to improve the prognosis for patients with KIT-mutated melanoma.
Authors: Richard D Carvajal; Cristina R Antonescu; Jedd D Wolchok; Paul B Chapman; Ruth-Ann Roman; Jerrold Teitcher; Katherine S Panageas; Klaus J Busam; Bartosz Chmielowski; Jose Lutzky; Anna C Pavlick; Anne Fusco; Lauren Cane; Naoko Takebe; Swapna Vemula; Nancy Bouvier; Boris C Bastian; Gary K Schwartz Journal: JAMA Date: 2011-06-08 Impact factor: 56.272
Authors: Carol Beadling; Erick Jacobson-Dunlop; F Stephen Hodi; Claudia Le; Andrea Warrick; Janice Patterson; Ajia Town; Amy Harlow; Frank Cruz; Sharl Azar; Brian P Rubin; Susan Muller; Rob West; Michael C Heinrich; Christopher L Corless Journal: Clin Cancer Res Date: 2008-11-01 Impact factor: 12.531
Authors: Anette Duensing; Fabiola Medeiros; Bryna McConarty; Nora E Joseph; Dipak Panigrahy; Samuel Singer; Christopher D M Fletcher; George D Demetri; Jonathan A Fletcher Journal: Oncogene Date: 2004-05-13 Impact factor: 9.867
Authors: B Liegl; I Kepten; C Le; M Zhu; G D Demetri; M C Heinrich; C D M Fletcher; C L Corless; J A Fletcher Journal: J Pathol Date: 2008-09 Impact factor: 7.996
Authors: Véronique Delmas; Friedrich Beermann; Silvia Martinozzi; Suzanne Carreira; Julien Ackermann; Mayuko Kumasaka; Laurence Denat; Jane Goodall; Flavie Luciani; Amaya Viros; Nese Demirkan; Boris C Bastian; Colin R Goding; Lionel Larue Journal: Genes Dev Date: 2007-11-15 Impact factor: 11.361
Authors: Charles D Blanke; George D Demetri; Margaret von Mehren; Michael C Heinrich; Burton Eisenberg; Jonathan A Fletcher; Christopher L Corless; Christopher D M Fletcher; Peter J Roberts; Daniela Heinz; Elisabeth Wehre; Zariana Nikolova; Heikki Joensuu Journal: J Clin Oncol Date: 2008-02-01 Impact factor: 44.544
Authors: Eric Blanc; Manuel Holtgrewe; Arunraj Dhamodaran; Clemens Messerschmidt; Gerald Willimsky; Thomas Blankenstein; Dieter Beule Journal: BMC Med Genomics Date: 2019-11-27 Impact factor: 3.063