Crizotinib-Resistant ROS1 Mutations Reveal a Predictive Kinase Inhibitor Sensitivity Model for ROS1- and ALK-Rearranged Lung Cancers

• Published in: Clinical cancer research 2016-12, Vol.22 (24), p.5983-5991
• Main Authors: Facchinetti, Francesco, Loriot, Yohann, Kuo, Mei-Shiue, Mahjoubi, Linda, Lacroix, Ludovic, Planchard, David, Besse, Benjamin, Farace, Françoise, Auger, Nathalie, Remon, Jordi, Scoazec, Jean-Yves, André, Fabrice, Soria, Jean-Charles, Friboulet, Luc
• Format: Article
• Language: English
• Subjects: Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; Cell Line, Tumor; Drug Resistance, Neoplasm - drug effects; Drug Resistance, Neoplasm - genetics; Humans; Lactams, Macrocyclic - therapeutic use; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Male; Middle Aged; Mutation - drug effects; Mutation - genetics; Oncogene Proteins, Fusion - genetics; Protein Kinase Inhibitors - therapeutic use; Protein-Tyrosine Kinases - genetics; Proto-Oncogene Proteins - genetics; Pyrazoles - therapeutic use; Pyridines - therapeutic use; Pyrimidines - therapeutic use; Receptor Protein-Tyrosine Kinases - genetics; Sulfones - therapeutic use
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.ccr-16-0917

The identification of molecular mechanisms conferring resistance to tyrosine kinase inhibitor (TKI) is a key step to improve therapeutic results for patients with oncogene addiction. Several alterations leading to EGFR and anaplastic lymphoma kinase (ALK) resistance to TKI therapy have been described in non-small cell lung cancer (NSCLC). Only two mutations in the ROS1 kinase domain responsible for crizotinib resistance have been described in patients thus far. A patient suffering from a metastatic NSCLC harboring an ezrin (EZR)-ROS1 fusion gene developed acquired resistance to the ALK/ROS1 inhibitor crizotinib. Molecular analysis (whole-exome sequencing, CGH) and functional studies were undertaken to elucidate the mechanism of resistance. Based on this case, we took advantage of the structural homology of ROS1 and ALK to build a predictive model for drug sensitivity regarding future ROS1 mutations. Sequencing revealed a dual mutation, S1986Y and S1986F, in the ROS1 kinase domain. Functional in vitro studies demonstrated that ROS1 harboring either the S1986Y or the S1986F mutation, while conferring resistance to crizotinib and ceritinib, was inhibited by lorlatinib (PF-06463922). The patient's clinical response confirmed the potency of lorlatinib against S1986Y/F mutations. The ROS1 S1986Y/F and ALK C1156Y mutations are homologous and displayed similar sensitivity patterns to ALK/ROS1 TKIs. We extended this analogy to build a model predicting TKI efficacy against potential ROS1 mutations. Clinical evidence, in vitro validation, and homology-based prediction provide guidance for treatment decision making for patients with ROS1-rearranged NSCLC who progressed on crizotinib. Clin Cancer Res; 22(24); 5983-91. ©2016 AACR.