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

Anti-EGFR antibodies such as cetuximab are active against KRAS/NRAS wild-type colorectal cancers (CRC) but acquired resistance invariably evolves. Which mutational mechanisms enable resistance evolution and whether adaptive mutagenesis, a transient cetuximab-induced increase in mutation generation, contributes in patients is unknown. Here, we investigate this in exome sequencing data of 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 for shorter progression free survival and for the evolution of these specific mutations during subsequent cetuximab treatment. This suggests that chemotherapy mutagenesis can accelerate resistance evolution. Mutational signatures may be a new class of cancer evolution predictor.