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CHK1 Inhibitor Blocks Phosphorylation of FAM122A and Promotes Replication Stress
Molecular Cell ( IF 16.0 ) Pub Date : 2020-10-26 , DOI: 10.1016/j.molcel.2020.10.008
Feng Li 1 , David Kozono 1 , Peter Deraska 2 , Timothy Branigan 3 , Connor Dunn 2 , Xiao-Feng Zheng 1 , Kalindi Parmar 2 , Huy Nguyen 2 , James DeCaprio 3 , Geoffrey I Shapiro 4 , Dipanjan Chowdhury 1 , Alan D D'Andrea 2
Affiliation  

While effective anti-cancer drugs targeting the CHK1 kinase are advancing in the clinic, drug resistance is rapidly emerging. Here, we demonstrate that CRISPR-mediated knockout of the little-known gene FAM122A/PABIR1 confers cellular resistance to CHK1 inhibitors (CHK1is) and cross-resistance to ATR inhibitors. Knockout of FAM122A results in activation of PP2A-B55α, a phosphatase that dephosphorylates the WEE1 protein and rescues WEE1 from ubiquitin-mediated degradation. The resulting increase in WEE1 protein expression reduces replication stress, activates the G2/M checkpoint, and confers cellular resistance to CHK1is. Interestingly, in tumor cells with oncogene-driven replication stress, CHK1 can directly phosphorylate FAM122A, leading to activation of the PP2A-B55α phosphatase and increased WEE1 expression. A combination of a CHK1i plus a WEE1 inhibitor can overcome CHK1i resistance of these tumor cells, thereby enhancing anti-cancer activity. The FAM122A expression level in a tumor cell can serve as a useful biomarker for predicting CHK1i sensitivity or resistance.



中文翻译:

CHK1 抑制剂阻断 FAM122A 的磷酸化并促进复制压力

虽然针对 CHK1 激酶的有效抗癌药物正在临床上取得进展,但耐药性正在迅速出现。在这里,我们证明了 CRISPR 介导的鲜为人知的基因 FAM122A/PABIR1 的敲除赋予细胞对 CHK1 抑制剂 (CHK1is) 的抗性和对 ATR 抑制剂的交叉抗性。FAM122A 的敲除导致 PP2A-B55α 的激活,PP2A-B55α 是一种磷酸酶,可将 WEE1 蛋白去磷酸化,并将 WEE1 从泛素介导的降解中拯救出来。WEE1 蛋白表达的增加减少了复制压力,激活了 G2/M 检查点,并赋予细胞对 CHK1is 的抗性。有趣的是,在具有癌基因驱动的复制应激的肿瘤细胞中,CHK1 可以直接磷酸化 FAM122A,导致 PP2A-B55α 磷酸酶的激活和 WEE1 表达增加。CHK1i 和 WEE1 抑制剂的组合可以克服这些肿瘤细胞的 CHK1i 耐药性,从而增强抗癌活性。肿瘤细胞中的 FAM122A 表达水平可作为预测 CHK1i 敏感性或耐药性的有用生物标志物。

更新日期:2020-11-06
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