Synergistic anticancer effect by targeting CDK2 and EGFR-ERK signaling

J Cell Biol. 2024 Jan 1;223(1):e202203005. doi: 10.1083/jcb.202203005. Epub 2023 Nov 13.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Proliferation
  • Cell Survival
  • Cyclin-Dependent Kinase 2 / antagonists & inhibitors
  • ErbB Receptors / antagonists & inhibitors
  • Humans
  • MAP Kinase Signaling System*
  • Neoplasms* / drug therapy
  • Signal Transduction*

Substances

  • CDK2 protein, human
  • Cyclin-Dependent Kinase 2
  • EGFR protein, human
  • ErbB Receptors
  • USP37 protein, human