Genomic and transcriptomic determinants of therapy resistance and immune landscape evolution during anti-EGFR treatment in colorectal cancer

Despite biomarker stratification, the anti-EGFR antibody cetuximab is only effective against a subgroup of colorectal cancers (CRC). This genomic and transcriptomic analysis of the cetuximab resistance landscape in 35 RAS wild-type CRCs identified associations of NF-1 and non-canonical RAS/RAF-aberrations with primary resistance and validated transcriptomic CRC-subtypes as non-genetic predictors of benefit. 64% of biopsies with acquired resistance harbored no genetic resistance drivers. Most of these had switched from a cetuximab-sensitive transcriptomic subtype pre-treatment 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 PDL1 and LAG3 immune-checkpoint expression, potentially providing opportunities to treat cetuximab-resistant CRCs with immunotherapy.

Type: Other
Archiver: European Genome-Phenome Archive (EGA)

1 Dataset 3 Publications

Click on a Dataset ID in the table below to learn more, and to find out who to contact about access to these data

Dataset ID	Description	Technology	Samples
EGAD00001004501	Genomic and transcriptomic data from a cohort of 35 RAS wild-type colorectal cancers. All 35 cases were DNA sequenced at baseline (BL) before treatment with single agent cetuximab. Progressive disease (PD)-biopsies were taken shortly after radiological progression and successfully exome sequenced from 24/35 cases. mRNA sequencing is available for 25 Baseline and 15 PD samples. ctDNA from 9 cases that progressed after prolonged cetuximab benefit were also deep sequenced.	HiSeq X Ten Illumina HiSeq 2000 Illumina HiSeq 2500	155

Publications	Citations
Genomic and Transcriptomic Determinants of Therapy Resistance and Immune Landscape Evolution during Anti-EGFR Treatment in Colorectal Cancer. 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. Cancer Cell 36: 2019 35-50.e9	120
Diagnostic Accuracy and Safety of Coaxial System in Oncology Patients Treated in a Specialist Cancer Center With Prospective Validation Within Clinical Trial Data. Khan K, Gonzalez-Exposito R, Cunningham D, Koh DM, Woolston A, Barber L, Griffiths B, Kouvelakis K, Calamai V, Bali M, Khan N, Bryant A, Saffery C, Dearman C, Begum R, Rao S, Starling N, Watkins D, Chau I, Braconi C, Valeri N, Gerlinger M, Fotiadis N. Front Oncol 10: 2020 1634	2
Mutational signatures impact the evolution of anti-EGFR antibody resistance in colorectal cancer. Woolston A, Barber LJ, Griffiths B, Pich O, Lopez-Bigas N, Matthews N, Rao S, Watkins D, Chau I, Starling N, Cunningham D, Gerlinger M. Nat Ecol Evol 5: 2021 1024-1032	14