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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Anaplastic Lymphoma Kinase / chemistry
  • Anaplastic Lymphoma Kinase / genetics*
  • Biomarkers, Tumor
  • Carcinoma, Non-Small-Cell Lung / diagnosis
  • Carcinoma, Non-Small-Cell Lung / drug therapy
  • Carcinoma, Non-Small-Cell Lung / genetics*
  • Computational Biology / methods
  • DNA Copy Number Variations
  • Drug Resistance, Neoplasm / genetics*
  • Female
  • High-Throughput Nucleotide Sequencing
  • Humans
  • In Situ Hybridization, Fluorescence
  • Lung Neoplasms / diagnosis
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / genetics*
  • Male
  • Middle Aged
  • Models, Molecular
  • Molecular Targeted Therapy
  • Mutation
  • Oncogene Proteins, Fusion* / chemistry
  • Oncogene Proteins, Fusion* / genetics
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Kinase Inhibitors / therapeutic use
  • Protein-Tyrosine Kinases / chemistry
  • Protein-Tyrosine Kinases / genetics*
  • Proto-Oncogene Proteins / chemistry
  • Proto-Oncogene Proteins / genetics*
  • Structure-Activity Relationship
  • Young Adult


  • Biomarkers, Tumor
  • Oncogene Proteins, Fusion
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins
  • ALK protein, human
  • Anaplastic Lymphoma Kinase
  • Protein-Tyrosine Kinases
  • ROS1 protein, human