Genomic and Transcriptomic Determinants of Therapy Resistance and Immune Landscape Evolution during Anti-EGFR Treatment in Colorectal Cancer

Cancer Cell. 2019 Jul 8;36(1):35-50.e9. doi: 10.1016/j.ccell.2019.05.013.


Despite biomarker stratification, the anti-EGFR antibody cetuximab is only effective against a subgroup of colorectal cancers (CRCs). This genomic and transcriptomic analysis of the cetuximab resistance landscape in 35 RAS wild-type CRCs identified associations of NF1 and non-canonical RAS/RAF aberrations with primary resistance and validated transcriptomic CRC subtypes as non-genetic predictors of benefit. Sixty-four percent of biopsies with acquired resistance harbored no genetic resistance drivers. Most of these had switched from a cetuximab-sensitive transcriptomic subtype at baseline to a fibroblast- and growth factor-rich subtype at progression. Fibroblast-supernatant conferred cetuximab resistance in vitro, confirming a major role for non-genetic resistance through stromal remodeling. Cetuximab treatment increased cytotoxic immune infiltrates and PD-L1 and LAG3 immune checkpoint expression, potentially providing opportunities to treat cetuximab-resistant CRCs with immunotherapy.

Keywords: EGFR; cancer evolution; cancer genomics; cancer-associated fibroblasts; cetuximab; colorectal cancer; drug resistance mechanisms; immunotherapy; molecular subtype; predictive biomarker.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents, Immunological / pharmacology
  • Antineoplastic Agents, Immunological / therapeutic use
  • Biomarkers, Tumor
  • Biopsy
  • Colorectal Neoplasms / drug therapy
  • Colorectal Neoplasms / etiology*
  • Colorectal Neoplasms / mortality
  • Colorectal Neoplasms / pathology
  • Computational Biology / methods
  • DNA Mutational Analysis
  • Drug Resistance, Neoplasm / genetics*
  • ErbB Receptors / antagonists & inhibitors
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Humans
  • Immunity*
  • Kaplan-Meier Estimate
  • Molecular Targeted Therapy
  • Mutation
  • Prognosis
  • Transcriptome*
  • Treatment Outcome


  • Antineoplastic Agents, Immunological
  • Biomarkers, Tumor
  • EGFR protein, human
  • ErbB Receptors