CRISPR/Cas9 genome-wide loss-of-function screening identifies druggable cellular factors involved in sunitinib resistance in renal cell carcinoma.
CRISPR/Cas9 genome-wide loss-of-function screening identifies druggable cellular factors involved in sunitinib resistance in renal cell carcinoma.
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DOI：
10.1038/s41416-020-01087-x
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发表时间：
2020-12
影响因子：
8.8
通讯作者：
Kolenko VM
中科院分区：
文献类型：
--
作者：
Makhov P;Sohn JA;Serebriiskii IG;Fazliyeva R;Khazak V;Boumber Y;Uzzo RG;Kolenko VM
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。然而，相当数量的ccRCC患者主要对靶向治疗难治，既没有显示疾病稳定也没有显示临床益处。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舒尼替尼治疗合成致死的可药物化分子因子。我们的筛选鉴定出法尼基转移酶是导致ccRCC中舒尼替尼耐药的最重要的命中物之一。与法尼基转移酶抑制剂lonafarnib的联合治疗有效地增强了舒尼替尼在体外和体内的抗肿瘤疗效。CRISPR/Cas9 LOF筛选提供了一种有希望的方法来鉴定和靶向参与抗癌治疗抗性的细胞因子。
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. 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. 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. CRISPR/Cas9 LOF screening presents a promising approach to identify and target cellular factors involved in the resistance to anti-cancer therapeutics.
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影响因子：
6.2
作者：
Kauh J;Chanel-Vos C;Escuin D;Fanucchi MP;Harvey RD;Saba N;Shin DM;Gal A;Pan L;Kutner M;Ramalingam SS;Bender L;Marcus A;Giannakakou P;Khuri FR
通讯作者：
Khuri FR
DOI：
10.1007/s13402-015-0218-8
发表时间：
2015-04
期刊：
Cellular oncology (Dordrecht, Netherlands)
影响因子：
--
作者：
Gotink KJ;Rovithi M;de Haas RR;Honeywell RJ;Dekker H;Poel D;Azijli K;Peters GJ;Broxterman HJ;Verheul HM
通讯作者：
Verheul HM
影响因子：
5.7
作者：
Makhov PB;Golovine K;Kutikov A;Teper E;Canter DJ;Simhan J;Uzzo RG;Kolenko VM
通讯作者：
Kolenko VM
影响因子：
4.8
作者：
Castro, AF;Rebhun, JF;Quilliam, LA
通讯作者：
Quilliam, LA
影响因子：
9.2
作者：
Long, X;Lin, Y;Avruch, J
通讯作者：
Avruch, J