对化疗的耐药性一直是限制多种癌症治疗效果的主要障碍。在这里，我们通过对多种癌细胞中的七种化疗药物进行 30 次基因组规模的 CRISPR 敲除筛选，系统地识别了化疗耐药性的遗传驱动因素。化疗耐药基因在不同条件下有所不同，主要是由于不同的遗传背景和药物作用机制，表现出异质和多重的化疗耐药途径。通过关注结直肠癌中的奥沙利​​铂和伊立替康耐药性，我们揭示了进化上独特的化疗耐药性可以共享通过 26 次第二轮 CRISPR 筛选和可药物基因库确定的共识漏洞。我们进一步确定 PLK4 作为治疗靶点，通过基因消除或药理学抑制来克服各种模型中的奥沙利​​铂耐药性，强调了对抗进化上独特的化学耐药性的单药策略。我们的研究不仅为化学耐药性的分子基础提供了资源和见解，而且还提出了针对这种耐药性的潜在生物标志物和治疗策略。© 2024。作者。

Resistance to chemotherapy has been a major hurdle that limits therapeutic benefits for many types of cancer. Here we systematically identify genetic drivers underlying chemoresistance by performing 30 genome-scale CRISPR knockout screens for seven chemotherapeutic agents in multiple cancer cells. Chemoresistance genes vary between conditions primarily due to distinct genetic background and mechanism of action of drugs, manifesting heterogeneous and multiplexed routes towards chemoresistance. By focusing on oxaliplatin and irinotecan resistance in colorectal cancer, we unravel that evolutionarily distinct chemoresistance can share consensus vulnerabilities identified by 26 second-round CRISPR screens with druggable gene library. We further pinpoint PLK4 as a therapeutic target to overcome oxaliplatin resistance in various models via genetic ablation or pharmacological inhibition, highlighting a single-agent strategy to antagonize evolutionarily distinct chemoresistance. Our study not only provides resources and insights into the molecular basis of chemoresistance, but also proposes potential biomarkers and therapeutic strategies against such resistance.© 2024. The Author(s).