Genomic and Transcriptomic Determinants of Therapy Resistance and Immune Landscape Evolution during Anti-EGFR Treatment in Colorectal Cancer.
Cancer Cell
; 36(1): 35-50.e9, 2019 07 08.
Article
de En
| MEDLINE
| ID: mdl-31287991
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.
Mots clés
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Tumeurs colorectales
/
Régulation de l'expression des gènes tumoraux
/
Résistance aux médicaments antinéoplasiques
/
Transcriptome
/
Immunité
Type d'étude:
Prognostic_studies
Limites:
Humans
Langue:
En
Journal:
Cancer Cell
Sujet du journal:
NEOPLASIAS
Année:
2019
Type de document:
Article
Pays d'affiliation:
Royaume-Uni