Targeting a chemo-induced adaptive signaling circuit confers therapeutic vulnerabilities in pancreatic cancer

Area of Science:

• Oncology
• Cancer Biology
• Molecular Signaling

Background:

• Advanced pancreatic ductal adenocarcinomas (PDAC) exhibit poor therapeutic response.
• Current treatments, including chemotherapy and immunotherapy, are largely ineffective for late-stage PDAC.
• Novel therapeutic strategies are urgently needed to overcome treatment resistance in PDAC.

Purpose of the Study:

• To investigate the signaling networks responsible for PDAC's poor response to therapy.
• To identify key molecular targets within these networks for therapeutic intervention.
• To evaluate the efficacy of co-targeting identified pathways in preclinical models and patient data.

Main Methods:

• Integration of single-cell transcriptomic data from PDAC mouse models and clinical patient data.
• Identification of Yap1 (cancer cells) and Cox2 (stromal fibroblasts) as key nodes in a chemo-induced signaling circuit.
• Preclinical evaluation of co-targeting Yap1 and Cox2 in combination with Gemcitabine in PDAC mouse models.
• Retrospective analysis of PDAC patient data correlating treatment with survival outcomes.

Main Results:

• A novel chemo-induced symbiotic signaling circuit conferring chemoresistance was identified, involving Yap1 in cancer cells and Cox2 in stromal fibroblasts.
• Co-targeting Yap1 and Cox2 in both cancer cells and stroma sensitized PDAC to Gemcitabine, significantly prolonging survival in mice.
• Inhibition of Yap1 (e.g., Statins) and Cox2 (e.g., Aspirin) alongside Gemcitabine in patient data correlated with markedly improved survival.

Conclusions:

• Chemotherapy induces an adaptive resistance circuit in PDAC involving Yap1 and Cox2.
• Co-targeting this circuit in both tumor cells and the tumor stroma represents a promising therapeutic strategy for advanced PDAC.
• Statins and Aspirin, in combination with chemotherapy, offer a potential novel treatment approach for PDAC patients.