Background: Anti-EGFR antibodies such as cetuximab are active against KRAS/NRAS wild-type colorectal cancers (CRC) but acquired resistance invariably evolves. Biomarkers that can be assessed prior to treatment to predict the time to resistance and the genetic resistance mechanisms that will evolve have not been identified. Distinct mutational signatures have been described in cancer and differences in their activity between tumours may influence resistance acquisitions. We investigated which mutational mechanisms enable cetuximab resistance evolution and whether adaptive mutagenesis, a recently described drug-induced transient increase in mutation generation, contributes to cetuximab resistance in a clinical trial. Patients and Methods: Patients with metastatic KRAS/NRAS wild-type colorectal cancers had been treated with the anti-EGFR antibody cetuximab in the Prospect-C phase II trial. We investigated mutational signatures and mutation loads in exome sequencing data from 42 biopsies that had been taken before treatment initiation or at progression. Results: Mutation loads did not increase from baseline to progression and evidence for a contribution of drug-induced mutagenesis was limited. However, the mutational Signature 17 was the main contributor of specific KRAS/NRAS and EGFR driver mutations that are typically enriched at acquired cetuximab resistance. Signature 17 activity before treatment predicted for shorter progression free survival and for the evolution of these specific mutations during subsequent cetuximab treatment. Conclusions: These data demonstrate the utility of mutational signatures as a new class of cancer evolution predictors. Targeting the underlying mutational process may provide opportunities to delay resistance acquisition.

中文翻译：

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突变过程影响大肠癌抗EGFR抗体耐药性的演变

背景：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演变。尚未确定可在治疗前进行评估以预测耐药性时间的生物标志物以及将进化的遗传耐药性机制。已经在癌症中描述了不同的突变特征，并且它们在肿瘤之间的活性差异可能会影响耐药性的获得。我们研究了哪些突变机制使西妥昔单抗耐药性得以发展，以及在临床试验中，自适应诱变（最近描述的药物诱导的突变发生瞬时增加）是否有助于西妥昔单抗耐药。患者和方法：在Prospect-C II期临床试验中，已用抗EGFR抗体西妥昔单抗治疗了转移性KRAS / NRAS野生型结直肠癌患者。我们调查了在治疗开始之前或进行中的42次活检中外显子组测序数据中的突变特征和突变负荷。结果：突变量没有从基线增加到进展，并且药物诱变的贡献的证据有限。但是，突变签名17是特定KRAS / NRAS和EGFR驱动程序突变的主要贡献者，这些突变通常在获得性西妥昔单抗耐药性时富集。治疗前的信号17活性可预测较短的无进展生存期以及随后西妥昔单抗治疗期间这些特定突变的演变。结论：这些数据证明了突变签名作为一类新的癌症演变预测因子的实用性。靶向潜在的突变过程可能提供延迟耐药性获得的机会。