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