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

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

Author information

1
Translational Oncogenomics Lab, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK.
2
GI Cancer Unit, The Royal Marsden Hospital, London SW3 6JJ, UK.
3
Centre for Evolution and Cancer Bioinformatics Team, The Institute of Cancer Research, London SW3 6JB, UK.
4
Cancer Institute, University College London, London WC1E 6AG, UK.
5
Tumour Microenvironment Lab, The Institute of Cancer Research, London SW3 6JB, UK.
6
Department of Radiology, The Royal Marsden Hospital, London SW3 6JJ, UK.
7
Departments of Pathology and Histopathology, University College Hospital, London NW1 2PG, UK.
8
Barts Cancer Institute, Queen Mary University, London EC1M 6BQ, UK.
9
Division of Structural Biology, The Institute of Cancer Research, London SW3 6JB, UK.
10
Systems and Precision Cancer Medicine Lab, The Institute of Cancer Research, London SW3 6JB, UK.
11
Translational Oncogenomics Lab, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK; GI Cancer Unit, The Royal Marsden Hospital, London SW3 6JJ, UK. Electronic address: marco.gerlinger@icr.ac.uk.

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.

KEYWORDS:

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

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