Synergistic anticancer effect by targeting CDK2 and EGFR–ERK signaling

• DOI: 10.1083/jcb.202203005
• Publication Date: 2023-11-13T14:49:10Z
• Authors: Jinhuan Wu; Yuping Chen; Rui Li; Yaping Guan; Mu Chen; Hui Yin; Xiaoning Yang; Mingpeng Jin; Bingsong Huang; Xin Ding; Jie Yang; Zhe Wang; Yiming He; Qianwen Wang; Jian Luo; Ping Wang; Zhiyong Mao; Michael S.Y. Huen; Zhenkun Lou; Jian Yuan; Fanghua Gong
• Keywords: ErbB Receptors; Cell Survival; MAP Kinase Signaling System; Neoplasms; Cyclin-Dependent Kinase 2; Humans; Animals; Article; 3. Good health; Cell Proliferation; Signal Transduction

The EGFR-RAS-ERK pathway is one of the most important signaling cascades in cell survival, growth, and proliferation. Aberrant activation this a common mechanism various cancers. Here, we report that CDK2 novel regulator ERK via USP37 deubiquitinase (DUB). Mechanistically, phosphorylates USP37, which required for DUB activity. Further, deubiquitinates stabilizes ERK1/2, thereby enhancing cancer Thus, able to promote proliferation by activating and, turn, stabilizing ERK1/2. Importantly, combined CDK1/2 EGFR inhibitors have synergetic anticancer effect through downregulation ERK1/2 stability Indeed, our patient-derived xenograft (PDX) results suggest targeting both activity kills cells more efficiently even at lower doses these two inhibitors, may reduce their associated side effects indicate potential new combination strategy therapy.