Synergistic anticancer effect by targeting CDK2 and EGFR-ERK signaling
Jinhuan Wu1,2, Yuping Chen1,2, Rui Li1,2
1Research Center for Translational Medicine, East Hospital, Tongji University School of Medicine, Shanghai, China.
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.
Insights
Cyclin-dependent kinase 2 (CDK2) regulates the ERK pathway by activating USP37, which stabilizes ERK1/2, promoting cancer cell proliferation. Combining CDK1/2 and EGFR inhibitors offers a synergistic anticancer strategy.
Area of Science:
- Molecular Biology
- Cancer Signaling Pathways
- Cellular Regulation
Background:
- The Epidermal Growth Factor Receptor (EGFR)-RAS-ERK signaling pathway is crucial for cell survival, growth, and proliferation.
- Aberrant activation of the EGFR-RAS-ERK pathway is a hallmark of many cancers, driving tumorigenesis.
- Understanding regulators of this pathway is key to developing effective cancer therapies.
Purpose of the Study:
- To identify novel regulators of the ERK pathway.
- To elucidate the mechanism by which CDK2 influences ERK signaling.
- To explore the therapeutic potential of targeting CDK2 and EGFR in cancer.
Main Methods:
- Investigated the interaction between CDK2, USP37, and ERK1/2.
- Utilized biochemical assays to determine the role of CDK2 phosphorylation in USP37 deubiquitinase (DUB) activity.
- Assessed the impact of USP37 on ERK1/2 stability and cancer cell proliferation.
- Evaluated the synergistic anticancer effects of combined CDK1/2 and EGFR inhibitors in patient-derived xenograft (PDX) models.
Main Results:
- CDK2 was identified as a novel regulator of the ERK pathway through its interaction with USP37.
- CDK2 phosphorylates USP37, enhancing its deubiquitinase activity.
- USP37 deubiquitinates and stabilizes ERK1/2, leading to increased cancer cell proliferation.
- Combined CDK1/2 and EGFR inhibition demonstrated synergistic anticancer effects by downregulating ERK1/2 stability and activity in PDX models.
Conclusions:
- CDK2 promotes cancer cell proliferation by activating USP37, which stabilizes ERK1/2.
- Targeting both CDK1/2 and EGFR simultaneously presents a promising combination therapy for cancer.
- This dual-targeting strategy enhances cancer cell killing efficiency and may reduce treatment-related side effects.
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