Genomic and Transcriptomic Determinants of Therapy Resistance and Immune Landscape Evolution during Anti-EGFR Treatment in Colorectal Cancer.
von Loga, K
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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.
Gene Expression Profiling
DNA Mutational Analysis
Gene Expression Regulation, Neoplastic
Drug Resistance, Neoplasm
Molecular Targeted Therapy
Antineoplastic Agents, Immunological
Gastrointestinal Cancers Clinical Trials
Medicine (RMH Smith Cunningham)
Systems and Precision Cancer Medicine
Structural Biology of Cell Signalling
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Cancer cell, 2019, 36 (1), pp. 35 - 50.e9