Journal article

RET Solvent Front Mutations Mediate Acquired Resistance to Selective RET Inhibition in RET-Driven Malignancies

Benjamin J Solomon, Lavinia Tan, Jessica J Lin, Stephen Q Wong, Sebastian Hollizeck, Kevin Ebata, Brian B Tuch, Satoshi Yoda, Justin F Gainor, Lecia V Sequist, Geoffrey R Oxnard, Oliver Gautschi, Alexander Drilon, Vivek Subbiah, Christine Khoo, Edward Y Zhu, Michele Nguyen, Dahlia Henry, Kevin R Condroski, Gabrielle R Kolakowski Show all

JOURNAL OF THORACIC ONCOLOGY | ELSEVIER SCIENCE INC | Published : 2020

Abstract

INTRODUCTION: Novel rearranged in transfection (RET)-specific tyrosine kinase inhibitors (TKIs) such as selpercatinib (LOXO-292) have shown unprecedented efficacy in tumors positive for RET fusions or mutations, notably RET fusion-positive NSCLC and RET-mutated medullary thyroid cancer (MTC). However, the mechanisms of resistance to these agents have not yet been described. METHODS: Analysis was performed of circulating tumor DNA and tissue in patients with RET fusion-positive NSCLC and RET-mutation positive MTC who developed disease progression after an initial response to selpercatinib. Acquired resistance was modeled preclinically using a CCDC6-RET fusion-positive NSCLC patient-derived xe..

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