抗癌药是癌症治疗的前沿，但是在三分之一到一半的病人中发生了先天性抗药性，使他们暴露在这些药物的副作用下，而没有实质利益。为了确定哪些基因和途径赋予了抗药性，我们在单倍体人类胚胎干细胞（hESCs）中进行了全基因组筛选。这些细胞具有一个基因的唯一副本，具有正常的核型，缺乏任何潜在的点突变的优势。我们最初展示了癌细胞系中抗癌药物的有效性与hESCs中的抗癌药物的有效性之间的密切相关性。然后，我们将包括五种不同药物疗法机制在内的10种抗癌药物暴露于所有编码蛋白质的基因的全基因组缺失功能库中。遗传筛选使我们能够识别赋予这些药物耐药性的基因和途径，证明了几个常见的途径。我们验证了一些耐药性基因，证明了有效药物浓度的显著变化，表明这些基因对特定药物具有药效。引人注目的是，p53信号通路似乎会导致对大量抗癌药物的耐药性。数据显示，失去p53会对许多药物的耐药性产生显著影响，但并非所有药物都会产生这种影响，因此在抗癌治疗之前需要对该基因的突变进行临床评估。 ©2023年作者。由北京干细胞和再生医学研究所和约翰威立公司出版的《细胞增殖》。

Anticancer drugs are at the frontline of cancer therapy. However, innate resistance to these drugs occurs in one-third to one-half of patients, exposing them to the side effects of these drugs with no meaningful benefit. To identify the genes and pathways that confer resistance to such therapies, we performed a genome-wide screen in haploid human embryonic stem cells (hESCs). These cells possess the advantage of having only one copy of each gene, harbour a normal karyotype, and lack any underlying point mutations. We initially show a close correlation between the potency of anticancer drugs in cancer cell lines to those in hESCs. We then exposed a genome-wide loss-of-function library of mutations in all protein-coding genes to 10 selected anticancer drugs, which represent five different mechanisms of drug therapies. The genetic screening enabled us to identify genes and pathways which can confer resistance to these drugs, demonstrating several common pathways. We validated a few of the resistance-conferring genes, demonstrating a significant shift in the effective drug concentrations to indicate a drug-specific effect to these genes. Strikingly, the p53 signalling pathway seems to induce resistance to a large array of anticancer drugs. The data shows dramatic effects of loss of p53 on resistance to many but not all drugs, calling for clinical evaluation of mutations in this gene prior to anticancer therapy.© 2023 The Authors. Cell Proliferation published by Beijing Institute for Stem Cell and Regenerative Medicine and John Wiley & Sons Ltd.