The Azrieli Center for Stem Cells and Genetic Research, Department of Genetics, Silberman Institute of Life Sciences, The Hebrew University, Jerusalem, Israel.
Hadassah Stem Cell Research Center, Goldyne Savad Institute of Gene Therapy, Department of Obstetrics and Gynecology, Ein Kerem, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
Cell Prolif. 2023 Jun;56(6):e13475. doi: 10.1111/cpr.13475. Epub 2023 Apr 21.
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.
抗癌药物是癌症治疗的第一线。然而，三分之一到一半的患者对这些药物存在先天耐药性，使他们面临这些药物的副作用，却没有任何有意义的益处。为了确定赋予这些治疗方法耐药性的基因和途径，我们在单倍体人胚胎干细胞（hESC）中进行了全基因组筛选。这些细胞具有每个基因只有一份拷贝的优势，具有正常的核型，并且没有任何潜在的点突变。我们最初表明，抗癌药物在癌细胞系中的效力与 hESC 中的效力密切相关。然后，我们将所有编码蛋白基因的全基因组功能丧失突变文库暴露于 10 种选定的抗癌药物中，这些药物代表五种不同的药物治疗机制。遗传筛选使我们能够鉴定出可赋予这些药物耐药性的基因和途径，证明了几种常见的途径。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，表明这些基因对这些药物具有特异性作用。引人注目的是，p53 信号通路似乎会导致对多种抗癌药物的耐药性。数据显示，p53 缺失对许多但不是所有药物的耐药性有显著影响，呼吁在抗癌治疗前对该基因的突变进行临床评估。
