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Deprivation of EGFR signal causes senolysis in PDAC with CDK4/6 inhibition
Yuanyuan Zhang1, Susumu Kohno1, Keqi Gao2
1Division of Oncology and Molecular Biology, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa, Japan.
Abstract:
Approved KRAS inhibitors have shown limited therapeutic benefit over standard chemotherapy in PDAC and often encounter acquired resistance due to additional genetic alterations. RAS and RB1 functionally antagonize each other, which explains why RB1 is rarely mutated in KRAS-driven tumors. In PDAC cells, CDK4/6 inhibition induced cellular senescence accompanied by partial apoptosis. However, additional treatment with a senolytic agent or an ERK inhibitor promoted more efficient tumor cell elimination. While CDK4/6 inhibition downregulated KRAS activity, it concurrently upregulated EGFR signaling in a SASP and JNK-dependent manner. Deprivation of EGFR signaling after CDK4/6 inhibition triggered apoptosis in senescent cells in a manner similar to the treatment with a senolytic agent. In contrast, specific inhibition of KRAS induced modest enhancement of EGFR activity and SASP in a JNK-independent manner. Collectively, our study proposes that the CDK4/6 inhibitor may achieve greater therapeutic efficacy when combined with the EGFR inhibitor than KRAS inhibitor monotherapy.
Insights
Combining CDK4/6 inhibitors with EGFR inhibitors shows promise for pancreatic ductal adenocarcinoma (PDAC) treatment. This combination therapy may overcome resistance and improve tumor cell elimination compared to KRAS inhibitors alone.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Approved KRAS inhibitors offer limited benefit in pancreatic ductal adenocarcinoma (PDAC) and face acquired resistance.
- RAS and RB1 have an antagonistic relationship, explaining RB1's rarity in KRAS-driven tumors.
Purpose of the Study:
- To investigate the therapeutic potential of combining CDK4/6 inhibition with other agents in PDAC.
- To elucidate the mechanisms underlying resistance and sensitivity to KRAS and CDK4/6 inhibitors in PDAC.
Main Methods:
- Utilized CDK4/6 inhibition in PDAC cells, followed by treatment with senolytic agents or ERK inhibitors.
- Analyzed the impact of CDK4/6 inhibition on KRAS and EGFR signaling pathways.
- Investigated the role of SASP and JNK signaling in cellular response to treatments.
Main Results:
- CDK4/6 inhibition induced senescence and partial apoptosis in PDAC cells.
- Combined senolytic or ERK inhibition enhanced tumor cell elimination.
- CDK4/6 inhibition downregulated KRAS but upregulated EGFR signaling via SASP and JNK.
- EGFR inhibition post-CDK4/6 inhibition triggered apoptosis in senescent cells.
- KRAS inhibition alone showed modest EGFR activity enhancement.
Conclusions:
- CDK4/6 inhibition combined with EGFR inhibition may offer superior therapeutic efficacy in PDAC compared to KRAS inhibitor monotherapy.
- Targeting EGFR signaling is a viable strategy to enhance the anti-PDAC effects of CDK4/6 inhibitors.
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