Evolution and clinical impact of co-occurring genetic alterations in advanced-stage EGFR-mutant lung cancers

Nat Genet. 2017 Dec;49(12):1693-1704. doi: 10.1038/ng.3990. Epub 2017 Nov 6.

Abstract

A widespread approach to modern cancer therapy is to identify a single oncogenic driver gene and target its mutant-protein product (for example, EGFR-inhibitor treatment in EGFR-mutant lung cancers). However, genetically driven resistance to targeted therapy limits patient survival. Through genomic analysis of 1,122 EGFR-mutant lung cancer cell-free DNA samples and whole-exome analysis of seven longitudinally collected tumor samples from a patient with EGFR-mutant lung cancer, we identified critical co-occurring oncogenic events present in most advanced-stage EGFR-mutant lung cancers. We defined new pathways limiting EGFR-inhibitor response, including WNT/β-catenin alterations and cell-cycle-gene (CDK4 and CDK6) mutations. Tumor genomic complexity increases with EGFR-inhibitor treatment, and co-occurring alterations in CTNNB1 and PIK3CA exhibit nonredundant functions that cooperatively promote tumor metastasis or limit EGFR-inhibitor response. This study calls for revisiting the prevailing single-gene driver-oncogene view and links clinical outcomes to co-occurring genetic alterations in patients with advanced-stage EGFR-mutant lung cancer.

MeSH terms

  • Carcinoma, Non-Small-Cell Lung / drug therapy
  • Carcinoma, Non-Small-Cell Lung / genetics*
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Proliferation / genetics
  • Class I Phosphatidylinositol 3-Kinases / genetics
  • Clonal Evolution
  • Cyclin-Dependent Kinases / genetics
  • ErbB Receptors / antagonists & inhibitors
  • ErbB Receptors / genetics*
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Kaplan-Meier Estimate
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / pathology
  • Mutation*
  • Neoplasm Staging
  • Protein Kinase Inhibitors / pharmacology
  • Wnt Signaling Pathway / drug effects
  • Wnt Signaling Pathway / genetics
  • beta Catenin / genetics

Substances

  • CTNNB1 protein, human
  • Protein Kinase Inhibitors
  • beta Catenin
  • Class I Phosphatidylinositol 3-Kinases
  • PIK3CA protein, human
  • ErbB Receptors
  • Cyclin-Dependent Kinases