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Genomic and Transcriptomic Determinants of Therapy Resistance and Immune Landscape Evolution during Anti-EGFR

Andrew Woolston1, Khurum Khan2, Georgia Spain1

  • 1Translational Oncogenomics Lab, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK.

Cancer Cell
|July 10, 2019
PubMed

Insights

Cetuximab resistance in colorectal cancer (CRC) can be driven by genetic changes like NF1 or non-genetic factors such as stromal remodeling. Some resistant CRCs may benefit from immunotherapy.

Area of Science:

  • Oncology
  • Genomics
  • Transcriptomics

Background:

  • Anti-EGFR antibody cetuximab shows limited efficacy in colorectal cancers (CRCs) despite biomarker stratification.
  • Understanding resistance mechanisms is crucial for improving CRC treatment outcomes.

Purpose of the Study:

  • To investigate the genomic and transcriptomic landscape of cetuximab resistance in RAS wild-type colorectal cancers.
  • To identify predictors of primary and acquired resistance to cetuximab.
  • To explore potential therapeutic strategies for cetuximab-resistant CRCs.

Main Methods:

  • Genomic and transcriptomic analysis of 35 RAS wild-type colorectal cancer (CRC) samples.
  • Assessment of primary and acquired resistance mechanisms.
  • In vitro validation using fibroblast supernatant.
  • Analysis of immune infiltrates and immune checkpoint expression.

Main Results:

  • NF1 and non-canonical RAS/RAF aberrations were associated with primary cetuximab resistance.
  • Transcriptomic CRC subtypes predicted benefit from cetuximab.
  • 64% of acquired resistance cases lacked genetic drivers, often showing a shift to a fibroblast-rich subtype.
  • Fibroblast supernatant conferred cetuximab resistance in vitro, highlighting stromal remodeling's role.
  • Cetuximab treatment increased cytotoxic immune cells and immune checkpoint expression (PD-L1, LAG3).

Conclusions:

  • Both genetic (NF1, RAS/RAF) and non-genetic (stromal remodeling) factors contribute to cetuximab resistance in CRC.
  • Transcriptomic subtypes are valuable non-genetic predictors of cetuximab response.
  • Emerging resistance mechanisms and immune modulation suggest potential for immunotherapy in resistant CRC.
Keywords:
EGFRcancer evolutioncancer genomicscancer-associated fibroblastscetuximabcolorectal cancerdrug resistance mechanismsimmunotherapymolecular subtypepredictive biomarker

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