Mutational signatures impact the evolution of anti-EGFR antibody resistance in colorectal cancer.
Andrew WoolstonLouise J BarberBeatrice GriffithsOriol PichNuria Lopez-BigasNik MatthewsSheela RaoDavid WatkinsIan ChauNaureen StarlingDavid CunninghamMarco GerlingerPublished in: Nature ecology & evolution (2021)
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.
Keyphrases
- wild type
- small cell lung cancer
- crispr cas
- epidermal growth factor receptor
- free survival
- end stage renal disease
- tyrosine kinase
- newly diagnosed
- chemotherapy induced
- chronic kidney disease
- ejection fraction
- genome wide
- squamous cell carcinoma
- copy number
- peritoneal dialysis
- single cell
- combination therapy
- papillary thyroid
- oxidative stress
- replacement therapy
- patient reported outcomes
- machine learning
- smoking cessation
- squamous cell
- cerebral ischemia
- artificial intelligence
- data analysis
- childhood cancer