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Use of a genome-wide haploid genetic screen to identify treatment predicting factors: a proof-of-principle study in pancreatic cancer

机译：全基因组单倍体遗传筛选在识别治疗预测因素中的应用：胰腺癌的一项原理验证研究

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The ability to develop a comprehensive panel of treatment predicting factors would significantly improve our ability to stratify patients for cytotoxic or targeted therapies, and prevent patients receiving ineffective treatments. We have investigated if a recently developed genome-wide haploid genetic screen can be used to reveal the critical mediators of response to anticancer therapy. Pancreatic cancer is known to be highly resistant to systemic therapy. Recently epigenetic changes have been shown to be a key determinant in the maintenance of subpopulations of cancer cells with high-level resistance to cytotoxic therapy. We show that in human pancreatic cancer cell lines, treatment with the potent class I histone deacetylase inhibitor, entinostat, synergistically enhances gemcitabine-induced inhibition of cell proliferation and apoptosis. Using a genome-wide haploid genetic screen, we identified deoxycytidine kinase (DCK) as one of the genes with the highest degree of insertional enrichment following treatment with gemcitabine and entinostat; DCK is already known to be the rate-limiting activating enzyme for gemcitabine. Immunoblotting confirmed loss of DCK protein expression in the resistant KBM7 cells. CRISPR/Cas-9 inactivation of DCK in pancreatic cancer cell lines resulted in resistance to gemcitabine alone and in combination with entinostat. We have identified gemcitabine and entinostat as a potential new combination therapy in pancreatic cancer, and in this proof-of-principle study we have demonstrated that a recently developed haploid genetic screen can be used as a novel approach to identify the critical genes that determine treatment response.
机译：开发全面的治疗预测因子的能力将显着提高我们对患者进行细胞毒性或靶向治疗的分层能力，并防止患者接受无效的治疗。我们已经研究了最近开发的全基因组单倍体遗传筛选是否可用于揭示抗癌治疗反应的关键介质。已知胰腺癌对全身治疗高度耐药。最近，表观遗传学改变已被证明是维持对细胞毒性疗法具有高水平抗性的癌细胞亚群的关键决定因素。我们显示，在人胰腺癌细胞系中，用有效的I类组蛋白脱乙酰基酶抑制剂，恩替司他治疗可协同增强吉西他滨诱导的细胞增殖和凋亡抑制作用。使用全基因组单倍体遗传筛选，我们确定脱氧胞苷激酶（DCK）是吉西他滨和恩替司他治疗后具有最高插入富集度的基因之一；已知DCK是吉西他滨的限速活化酶。免疫印迹证实抗性KBM7细胞中DCK蛋白表达的丧失。胰腺癌细胞系中DCK的CRISPR / Cas-9灭活导致单独对吉西他滨和与恩替司他联用产生耐药性。我们已经确定吉西他滨和恩替司他是胰腺癌的潜在新组合疗法，并且在这项原理验证研究中，我们已经证明，最近开发的单倍体遗传筛选可以用作鉴定决定治疗关键基因的新方法。响应。

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