Mutational signatures impact the evolution of anti-EGFR antibody resistance in colorectal cancer.

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Embargo End Date

ICR Authors

Woolston, Andrew
 Gerlinger, Marco

Authors

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

Document Type

Journal Article

Date

2021-05-20

Date Accepted

2021-04-20

Abstract

Anti-EGFR antibodies such as cetuximab are active against KRAS/NRAS wild-type colorectal cancers (CRCs), but acquired resistance invariably evolves. It is unknown which mutational mechanisms enable resistance evolution and whether adaptive mutagenesis (a transient cetuximab-induced increase in mutation generation) contributes in patients. Here, we investigate these questions in exome sequencing data from 42 baseline and progression biopsies from cetuximab-treated CRCs. Mutation loads did not increase from baseline to progression, and evidence for a contribution of adaptive mutagenesis was limited. However, the chemotherapy-induced mutational signature SBS17b was the main contributor of specific KRAS/NRAS and EGFR driver mutations that are enriched at acquired resistance. Detectable SBS17b activity before treatment predicted shorter progression-free survival and the evolution of these specific mutations during subsequent cetuximab treatment. This result suggests that chemotherapy mutagenesis can accelerate resistance evolution. Mutational signatures may be a new class of cancer evolution predictor.

Citation

Nature Ecology and Evolution

DOI

URI

https://repository.icr.ac.uk/handle/internal/4555

Rights

https://creativecommons.org/licenses/by/4.0

Source Title

Publisher

NATURE PORTFOLIO

ISSN

2397-334X

eISSN

Collections

Cancer Biology

Research Team

Medicine (RMH Smith Cunningham)
Translational Oncogenomics
Medicine (RMH Smith Cunningham)
Translational Oncogenomics

Notes