Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for DNA Damage and Repair, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
Mol Cell. 2020 Nov 5;80(3):410-422.e6. doi: 10.1016/j.molcel.2020.10.008. Epub 2020 Oct 26.
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.
虽然针对 CHK1 激酶的有效抗癌药物在临床上不断取得进展，但耐药性也迅速出现。在这里，我们证明了 CRISPR 介导的鲜为人知的基因 FAM122A/PABIR1 的敲除赋予了细胞对 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，可使 WEE1 蛋白去磷酸化，并阻止 WEE1 被泛素介导的降解。由此增加的 WEE1 蛋白表达减少复制应激，激活 G2/M 检查点，并赋予细胞对 CHK1is 的抗性。有趣的是，在具有致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 表达的增加。CHK1i 加 WEE1 抑制剂的组合可以克服这些肿瘤细胞对 CHK1i 的耐药性，从而增强抗癌活性。肿瘤细胞中 FAM122A 的表达水平可以作为预测 CHK1i 敏感性或耐药性的有用生物标志物。
