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.

西妥昔单抗等抗 EGFR 抗体对KRAS/NRAS野生型结直肠癌 (CRC) 具有活性，但获得性耐药总是会发生。目前尚不清楚哪些突变机制能够实现耐药性进化，以及适应性诱变（瞬时西妥昔单抗诱导的突变产生增加）是否有助于患者。在这里，我们在来自西妥昔单抗治疗的 CRC 的 42 个基线和进展活检的外显子组测序数据中调查这些问题。突变负荷从基线到进展没有增加，适应性诱变贡献的证据有限。然而，化疗诱导的突变特征 SBS17b 是特异性KRAS/NRAS和EGFR的主要贡献者在获得性抗性中富集的驱动突变。治疗前可检测到的 SBS17b 活性预示着更短的无进展生存期以及后续西妥昔单抗治疗期间这些特定突变的演变。该结果表明化学诱变可以加速耐药性进化。突变特征可能是一类新的癌症进化预测因子。