Division of General Thoracic Surgery, Inselspital, Bern University Hospital, University of Bern, Switzerland.
Department for BioMedical Research (DBMR), Inselspital, Bern University Hospital, University of Bern, Switzerland.
Cancer Res. 2021 Jun 1;81(11):3121-3133. doi: 10.1158/0008-5472.CAN-20-2276. Epub 2021 Mar 8.
Oncogenic activation of the FGFR pathway is frequent in lung and other cancers. However, due to drug resistance, pharmacological blockage of aberrant FGFR signaling has provided little clinical benefit in patients with -amplified tumors. The determining factors for the limited efficacy of FGFR-targeted therapy remain incompletely understood. In this study, we performed kinome-wide CRISPR/Cas9 loss-of-function screens in -amplified lung cancer cells treated with an FGFR inhibitor. These screens identified PLK1 as a potent synthetic lethal target that mediates a resistance mechanism by overriding DNA damage and cell-cycle arrest upon FGFR1 inhibition. Genetic and pharmacological antagonism of PLK1 in combination with FGFR inhibitor therapy synergized to enhance antiproliferative effects and drove cancer cell death and through activation of the γH2AX-CHK-E2F1 axis. These findings suggest a previously unappreciated role for PLK1 in modulating FGFR1 inhibitor sensitivity and demonstrate a synergistic drug combination for treating -amplified lung cancer. SIGNIFICANCE: The identification of PLK1 as a potent synthetic lethal target for FGFR-targeted therapy provides an innovative rationale for the treatment of lung and other -amplified cancers.
致癌性 FGFR 通路的激活在肺部和其他癌症中很常见。然而，由于耐药性，异常 FGFR 信号的药理学阻断在 - 扩增肿瘤患者中几乎没有提供临床益处。FGFR 靶向治疗疗效有限的决定因素仍不完全清楚。在这项研究中，我们在接受 FGFR 抑制剂治疗的 - 扩增肺癌细胞中进行了全激酶组 CRISPR/Cas9 功能丧失筛选。这些筛选确定 PLK1 是一个有效的合成致死靶点，通过在 FGFR1 抑制时绕过 DNA 损伤和细胞周期停滞，介导一种耐药机制。PLK1 的遗传和药理学拮抗与 FGFR 抑制剂治疗联合使用，通过激活 γH2AX-CHK-E2F1 轴，协同增强抗增殖作用并驱动癌细胞死亡。这些发现表明 PLK1 在调节 FGFR1 抑制剂敏感性方面具有以前未被认识的作用，并证明了一种用于治疗 - 扩增肺癌的协同药物组合。意义：将 PLK1 鉴定为 FGFR 靶向治疗的有效合成致死靶点，为治疗肺部和其他 - 扩增癌症提供了创新的理论基础。
