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Clin Cancer Res. 2018 Jul 15;24(14):3334-3347. doi: 10.1158/1078-0432.CCR-17-2452. Epub 2018 Apr 10.

Resistance Mechanisms to Targeted Therapies in ROS1+ and ALK+ Non-small Cell Lung Cancer.

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Division of Medical Oncology, UCSF Helen Diller Comprehensive Cancer Center, San Francisco, California.
Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
Department of Pediatrics, Section of Hematology, Oncology, and Bone Marrow Transplant, University of Colorado, Aurora, Colorado.
Department of Pathology, University of Colorado School of Medicine, Aurora, Colorado.
Department of Oncology and Radiotherapy, Medical University of Gdańsk, Gdańsk, Poland.


Purpose: Despite initial benefit from tyrosine kinase inhibitors (TKIs), patients with advanced non-small cell lung cancer (NSCLC) harboring ALK (ALK+) and ROS1 (ROS1+) gene fusions ultimately progress. Here, we report on the potential resistance mechanisms in a series of patients with ALK+ and ROS1+ NSCLC progressing on different types and/or lines of ROS1/ALK-targeted therapy.Experimental Design: We used a combination of next-generation sequencing (NGS), multiplex mutation assay, direct DNA sequencing, RT-PCR, and FISH to identify fusion variants/partners and copy-number gain (CNG), kinase domain mutations (KDM), and copy-number variations (CNVs) in other cancer-related genes. We performed testing on 12 ROS1+ and 43 ALK+ patients.Results: One of 12 ROS1+ (8%) and 15 of 43 (35%) ALK + patients harbored KDM. In the ROS1+ cohort, we identified KIT and β-catenin mutations and HER2-mediated bypass signaling as non-ROS1-dominant resistance mechanisms. In the ALK+ cohort, we identified a novel NRG1 gene fusion, a RET fusion, 2 EGFR, and 3 KRAS mutations, as well as mutations in IDH1, RIT1, NOTCH, and NF1 In addition, we identified CNV in multiple proto-oncogenes genes including PDGFRA, KIT, KDR, GNAS, K/HRAS, RET, NTRK1, MAP2K1, and others.Conclusions: We identified a putative TKI resistance mechanism in six of 12 (50%) ROS1 + patients and 37 of 43 (86%) ALK+ patients. Our data suggest that a focus on KDMs will miss most resistance mechanisms; broader gene testing strategies and functional validation is warranted to devise new therapeutic strategies for drug resistance. Clin Cancer Res; 24(14); 3334-47. ©2018 AACR.

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