Landscape of Acquired Resistance to Osimertinib in
| Autor: | Zofia, Piotrowska, Hideko, Isozaki, Jochen K, Lennerz, Justin F, Gainor, Inga T, Lennes, Viola W, Zhu, Nicolas, Marcoux, Mandeep K, Banwait, Subba R, Digumarthy, Wenjia, Su, Satoshi, Yoda, Amanda K, Riley, Varuna, Nangia, Jessica J, Lin, Rebecca J, Nagy, Richard B, Lanman, Dora, Dias-Santagata, Mari, Mino-Kenudson, A John, Iafrate, Rebecca S, Heist, Alice T, Shaw, Erica K, Evans, Corinne, Clifford, Sai-Hong I, Ou, Beni, Wolf, Aaron N, Hata, Lecia V, Sequist |
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| Rok vydání: | 2018 |
| Předmět: |
Adult
Male congenital hereditary and neonatal diseases and abnormalities endocrine system Lung Neoplasms endocrine system diseases Oncogene Proteins Fusion Article Cohort Studies Carcinoma Non-Small-Cell Lung Cell Line Tumor Humans neoplasms Protein Kinase Inhibitors Aged Aged 80 and over Acrylamides Aniline Compounds Proto-Oncogene Proteins c-ret Middle Aged respiratory tract diseases ErbB Receptors Cytoskeletal Proteins Drug Resistance Neoplasm Mutation Female |
| Zdroj: | Cancer discovery. 8(12) |
| ISSN: | 2159-8290 |
| Popis: | We present a cohort of 41 patients with osimertinib resistance biopsies, including two with an acquired CCDC6-RET fusion. While RET fusions have been identified in resistant EGFR-mutant NSCLC, their role in acquired resistance to EGFR inhibitors is not well described. To assess the biological implications of RET fusions in an EGFR-mutant cancer, we expressed CCDC6-RET in PC9 (EGFR del19) and MGH134 (EGFR L858R/T790M) cells and found that CCDC6-RET was sufficient to confer resistance to EGFR-TKIs. The selective RET inhibitors BLU-667 or cabozantinib resensitized CCDC6-RET-expressing cells to EGFR inhibition. Finally, we treated two patients with EGFR-mutant NSCLC and RET-mediated resistance with osimertinib and BLU-667. The combination was well-tolerated and led to rapid radiographic response in both patients. This study provides proof-of-concept that RET fusions can mediate acquired resistance to EGFR TKIs and that combined EGFR and RET inhibition with osimertinib/BLU-667 may be a well-tolerated and effective treatment strategy for such patients. |
| Databáze: | OpenAIRE |
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