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

TLDR

Cetuximab is effective only in a subset of colorectal cancers despite biomarker stratification. In 35 RAS‑wild‑type CRCs, primary resistance correlated with NF1 and non‑canonical RAS/RAF mutations and transcriptomic subtypes, while 64 % of acquired resistance lacked genetic drivers and often shifted to a fibroblast‑rich, growth‑factor‑laden subtype that conferred resistance in vitro, and cetuximab treatment boosted cytotoxic immune infiltrates and PD‑L1/LAG3 expression, hinting at immunotherapy options.

Abstract

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.