CRISPR/Cas9 全基因组功能丧失筛选鉴定出参与肾细胞癌舒尼替尼耐药的可药物治疗的细胞因子。
CRISPR/Cas9 genome-wide loss-of-function screening identifies druggable cellular factors involved in sunitinib resistance in renal cell carcinoma.
机构信息
Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA, USA.
Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, PA, USA.
出版信息
Br J Cancer. 2020 Dec;123(12):1749-1756. doi: 10.1038/s41416-020-01087-x. Epub 2020 Sep 24.
BACKGROUND
Multi-targeted tyrosine kinase inhibitors (TKIs) are the standard of care for patients with advanced clear cell renal cell carcinoma (ccRCC). However, a significant number of ccRCC patients are primarily refractory to targeted therapeutics, showing neither disease stabilisation nor clinical benefits.
METHODS
We used CRISPR/Cas9-based high-throughput loss of function (LOF) screening to identify cellular factors involved in the resistance to sunitinib. Next, we validated druggable molecular factors that are synthetically lethal with sunitinib treatment using cell and animal models of ccRCC.
RESULTS
Our screening identified farnesyltransferase among the top hits contributing to sunitinib resistance in ccRCC. Combined treatment with farnesyltransferase inhibitor lonafarnib potently augmented the anti-tumour efficacy of sunitinib both in vitro and in vivo.
CONCLUSION
CRISPR/Cas9 LOF screening presents a promising approach to identify and target cellular factors involved in the resistance to anti-cancer therapeutics.
背景
多靶点酪氨酸激酶抑制剂（TKI）是晚期透明细胞肾细胞癌（ccRCC）患者的标准治疗方法。然而，相当数量的 ccRCC 患者主要对靶向治疗具有抗性，既没有疾病稳定也没有临床获益。
方法
我们使用基于 CRISPR/Cas9 的高通量功能丧失（LOF）筛选来鉴定参与舒尼替尼耐药的细胞因子。接下来，我们使用 ccRCC 的细胞和动物模型验证了与舒尼替尼治疗具有合成致死性的可用药理学分子因子。
结果
我们的筛选发现法呢基转移酶是导致 ccRCC 对舒尼替尼耐药的主要因素之一。法呢基转移酶抑制剂 lonafarnib 与舒尼替尼联合治疗在体外和体内均能显著增强舒尼替尼的抗肿瘤疗效。
结论
CRISPR/Cas9 LOF 筛选为鉴定和靶向参与抗癌治疗耐药的细胞因子提供了一种很有前途的方法。
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