Genomic and Transcriptomic Determinants of Therapy Resistance and Immune Landscape Evolution during Anti-EGFR Treatment in Colorectal Cancer.
Date
2019-06-26ICR Author
Author
Woolston, A
Khan, K
Spain, G
Barber, LJ
Griffiths, B
Gonzalez-Exposito, R
Hornsteiner, L
Punta, M
Patil, Y
Newey, A
Mansukhani, S
Davies, MN
Furness, A
Sclafani, F
Peckitt, C
Jiménez, M
Kouvelakis, K
Ranftl, R
Begum, R
Rana, I
Thomas, J
Bryant, A
Quezada, S
Wotherspoon, A
Khan, N
Fotiadis, N
Marafioti, T
Powles, T
Lise, S
Calvo, F
Guettler, S
von Loga, K
Rao, S
Watkins, D
Starling, N
Chau, I
Sadanandam, A
Cunningham, D
Gerlinger, M
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Subject
Humans
Colorectal Neoplasms
Biopsy
Prognosis
Treatment Outcome
Gene Expression Profiling
DNA Mutational Analysis
Computational Biology
Immunity
Gene Expression Regulation, Neoplastic
Drug Resistance, Neoplasm
Mutation
Kaplan-Meier Estimate
Molecular Targeted Therapy
Transcriptome
ErbB Receptors
Biomarkers, Tumor
Antineoplastic Agents, Immunological
Research team
Gastrointestinal Cancers Clinical Trials
Medicine (RMH Smith Cunningham)
Systems and Precision Cancer Medicine
Translational Oncogenomics
Structural Biology of Cell Signalling
Language
eng
Date accepted
2019-05-23
License start date
2019-07
Citation
Cancer cell, 2019, 36 (1), pp. 35 - 50.e9
Publisher
CELL PRESS