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Genomic and Transcriptomic Determinants of Therapy Resistance and Immune Landscape Evolution during Anti-EGFR Treatment in Colorectal Cancer.
- Source :
-
Cancer cell [Cancer Cell] 2019 Jul 08; Vol. 36 (1), pp. 35-50.e9. - Publication Year :
- 2019
-
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.<br /> (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Antineoplastic Agents, Immunological pharmacology
Antineoplastic Agents, Immunological therapeutic use
Biomarkers, Tumor
Biopsy
Colorectal Neoplasms drug therapy
Colorectal Neoplasms mortality
Colorectal Neoplasms pathology
Computational Biology methods
DNA Mutational Analysis
ErbB Receptors antagonists & inhibitors
Gene Expression Profiling
Humans
Kaplan-Meier Estimate
Molecular Targeted Therapy
Mutation
Prognosis
Treatment Outcome
Colorectal Neoplasms etiology
Drug Resistance, Neoplasm genetics
Gene Expression Regulation, Neoplastic drug effects
Immunity
Transcriptome
Subjects
Details
- Language :
- English
- ISSN :
- 1878-3686
- Volume :
- 36
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Cancer cell
- Publication Type :
- Academic Journal
- Accession number :
- 31287991
- Full Text :
- https://doi.org/10.1016/j.ccell.2019.05.013