Genome-wide CRISPR-cas9 knockout screening identifies GRB7 as a driver for MEK inhibitor resistance in KRAS mutant colon cancer.
Genome-wide CRISPR-cas9 knockout screening identifies GRB7 as a driver for MEK inhibitor resistance in KRAS mutant colon cancer.
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全基因组 CRISPR-cas9 敲除筛选确定 GRB7 是 KRAS 突变结肠癌 MEK 抑制剂耐药性的驱动因素
DOI：
10.1038/s41388-021-02077-w
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发表时间：
2022-01
期刊：
影响因子：
8
通讯作者：
Shi H
中科院分区：
文献类型：
--
作者：
Yu C;Luo D;Yu J;Zhang M;Zheng X;Xu G;Wang J;Wang H;Xu Y;Jiang K;Xu J;Ma X;Jing J;Shi H
靶向KRAS通路是一种有希望但具有挑战性的结直肠癌治疗方法。尽管在braf突变的黑色素瘤中显示出强有力的疗效，但MEK抑制剂似乎由于其内在的代偿信号而被结直肠癌细胞耐受。在这里，我们在MEK抑制剂存在的情况下进行了全基因组CRISPR/Cas9筛选，以鉴定在携带KRAS突变的CRC模型中，MEK抑制可合成致死的基因。几个基因被鉴定为潜在的功能驱动因子，这些基因在grb7介导的RTK通路中显著富集。功能丧失和功能获得试验证实，GRB7通过RTK途径有效地使CRC细胞对MEK抑制剂产生原发性耐药性。GRB7免疫沉淀质谱分析显示，PLK1是GRB7的主要相互作用激酶。PLK1的抑制抑制了RTK的下游信号，包括FAK、STAT3、AKT和4EBP1。PLK1和MEK抑制剂联合使用在体外和体内可协同抑制结直肠癌细胞增殖并诱导凋亡。总之，我们确定GRB7-PLK1是介导rtk的关键轴，导致MEK抑制剂耐受。因此，PLK1是协同MEK抑制剂在临床治疗携带KRAS突变的结直肠癌患者中的一个有希望的靶点。
Targeting the KRAS pathway is a promising but challenging approach for colorectal cancer therapy. Despite showing potent efficacy in BRAF-mutated melanoma, MEK inhibitors appeared to be tolerated by colorectal cancer cells due to their intrinsic compensatory signaling. Here, we performed genome-wide CRISPR/Cas9 screening in the presence of MEK inhibitor to identify genes that are synthetically lethal with MEK inhibition in CRC models harboring KRAS mutations. Several genes were identified as potential functional drivers, which were significantly enriched in the GRB7-mediated RTK pathway. Loss-of-function and gain-of-function assays validated that GRB7 potently rendered CRC cells primary resistance to MEK inhibitors through the RTK pathway. Mass spectrum analysis of GRB7 immunoprecipitates revealed that PLK1 was the predominant interacting kinase of GRB7. Inhibition of PLK1 suppressed downstream signaling of RTK, including FAK, STAT3, AKT, and 4EBP1. The combination of PLK1 and MEK inhibitors synergistically inhibited CRC cell proliferation and induced apoptosis in vitro and in vivo. In conclusion, we identified GRB7-PLK1 as a pivotal axis mediating RTKs, resulting in MEK inhibitor tolerance. PLK1 is therefore a promising target for synergizing MEK inhibitors in the clinical treatment of CRC patients harboring KRAS mutations.
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影响因子：
28.2
作者：
Fedele C;Ran H;Diskin B;Wei W;Jen J;Geer MJ;Araki K;Ozerdem U;Simeone DM;Miller G;Neel BG;Tang KH
通讯作者：
Tang KH
影响因子：
4
作者：
Kirouac DC;Schaefer G;Chan J;Merchant M;Orr C;Huang SA;Moffat J;Liu L;Gadkar K;Ramanujan S
通讯作者：
Ramanujan S
影响因子：
51.1
作者：
Ascierto, Paolo A.;Schadendorf, Dirk;Dummer, Reinhard
通讯作者：
Dummer, Reinhard
全基因组的RNAi筛查鉴定了与RAS癌基因的多种合成致死相互作用。
影响因子：
64.5
作者：
Luo J;Emanuele MJ;Li D;Creighton CJ;Schlabach MR;Westbrook TF;Wong KK;Elledge SJ
通讯作者：
Elledge SJ
影响因子：
28.2
作者：
Corcoran RB;André T;Atreya CE;Schellens JHM;Yoshino T;Bendell JC;Hollebecque A;McRee AJ;Siena S;Middleton G;Muro K;Gordon MS;Tabernero J;Yaeger R;O'Dwyer PJ;Humblet Y;De Vos F;Jung AS;Brase JC;Jaeger S;Bettinger S;Mookerjee B;Rangwala F;Van Cutsem E
通讯作者：
Van Cutsem E