MAPK Pathway Alterations Correlate with Poor Survival and Drive Resistance to Therapy in Patients with Lung Cancers Driven by ROS1 Fusions

Clin Cancer Res. 2020 Jun 15;26(12):2932-2945. doi: 10.1158/1078-0432.CCR-19-3321. Epub 2020 Mar 2.


Purpose: ROS1 tyrosine kinase inhibitors (TKI) provide significant benefit in lung adenocarcinoma patients with ROS1 fusions. However, as observed with all targeted therapies, resistance arises. Detecting mechanisms of acquired resistance (AR) is crucial to finding novel therapies and improve patient outcomes.

Experimental design: ROS1 fusions were expressed in HBEC and NIH-3T3 cells either by cDNA overexpression (CD74/ROS1, SLC34A2/ROS1) or CRISPR-Cas9-mediated genomic engineering (EZR/ROS1). We reviewed targeted large-panel sequencing data (using the MSK-IMPACT assay) patients treated with ROS1 TKIs, and genetic alterations hypothesized to confer AR were modeled in these cell lines.

Results: Eight of the 75 patients with a ROS1 fusion had a concurrent MAPK pathway alteration and this correlated with shorter overall survival. In addition, the induction of ROS1 fusions stimulated activation of MEK/ERK signaling with minimal effects on AKT signaling, suggesting the importance of the MAPK pathway in driving ROS1 fusion-positive cancers. Of 8 patients, 2 patients harbored novel in-frame deletions in MEK1 (MEK1delE41_L54) and MEKK1 (MEKK1delH907_C916) that were acquired after ROS1 TKIs, and 2 patients harbored NF1 loss-of-function mutations. Expression of MEK1del or MEKK1del, and knockdown of NF1 in ROS1 fusion-positive cells activated MEK/ERK signaling and conferred resistance to ROS1 TKIs. Combined targeting of ROS1 and MEK inhibited growth of cells expressing both ROS1 fusion and MEK1del.

Conclusions: We demonstrate that downstream activation of the MAPK pathway can mediate of innate acquired resistance to ROS1 TKIs and that patients harboring ROS1 fusion and concurrent downstream MAPK pathway alterations have worse survival. Our findings suggest a treatment strategy to target both aberrations.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenocarcinoma of Lung / drug therapy
  • Adenocarcinoma of Lung / genetics
  • Adenocarcinoma of Lung / mortality*
  • Adenocarcinoma of Lung / pathology
  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Animals
  • Apoptosis
  • Biomarkers, Tumor / genetics
  • Carcinoma, Non-Small-Cell Lung / drug therapy
  • Carcinoma, Non-Small-Cell Lung / genetics
  • Carcinoma, Non-Small-Cell Lung / mortality*
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Cell Proliferation
  • Drug Resistance, Neoplasm*
  • Female
  • Follow-Up Studies
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / genetics
  • Lung Neoplasms / mortality
  • Lung Neoplasms / pathology
  • MAP Kinase Signaling System / drug effects*
  • Male
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Middle Aged
  • Mutation
  • Oncogene Proteins, Fusion / genetics*
  • Prognosis
  • Protein Kinase Inhibitors / therapeutic use*
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • Protein-Tyrosine Kinases / genetics*
  • Proto-Oncogene Proteins / antagonists & inhibitors
  • Proto-Oncogene Proteins / genetics*
  • Retrospective Studies
  • Survival Rate
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays
  • Young Adult


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