Genomic and Transcriptomic Determinants of Therapy Resistance and Immune Landscape Evolution during Anti-EGFR Treatment in Colorectal Cancer.
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Authors
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
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
Document Type
Journal Article
Date
2019-06-26
Date Accepted
2019-05-23
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.
Citation
Cancer cell, 2019, 36 (1), pp. 35 - 50.e9
Source Title
Publisher
CELL PRESS
ISSN
1535-6108
eISSN
1878-3686
Research Team
Gastrointestinal Cancers Clinical Trials
Medicine (RMH Smith Cunningham)
Systems and Precision Cancer Medicine
Translational Oncogenomics
Structural Biology of Cell Signalling
Medicine (RMH Smith Cunningham)
Systems and Precision Cancer Medicine
Translational Oncogenomics
Structural Biology of Cell Signalling