Autophagy Inhibition by Targeting PIKfyve Potentiates Response to Immune Checkpoint Blockade in Prostate Cancer

Area of Science:

• Oncology
• Cancer Immunology
• Molecular Biology

Background:

• Castration-resistant prostate cancer (CRPC) has limited treatment options.
• Multi-tyrosine kinase inhibitors (MTKIs) show restricted efficacy in CRPC.
• Novel therapeutic strategies are needed to overcome treatment resistance.

Purpose of the Study:

• To evaluate the anti-tumor activity and mechanism of action of ESK981, an orally bioavailable MTKI.
• To investigate ESK981's effect on the tumor immune microenvironment.
• To determine if ESK981 can enhance responses to immune checkpoint blockade.

Main Methods:

• Preclinical studies in diverse CRPC models.
• Assessment of tumor growth inhibition and immune cell infiltration.
• Identification of ESK981's direct molecular target using mechanistic studies.
• Evaluation of PIKfyve-knockdown effects.

Main Results:

• ESK981 demonstrated anti-tumor activity by decreasing tumor growth in CRPC models.
• ESK981 upregulated CXCL10 via the interferon gamma pathway, promoting T cell infiltration.
• PIKfyve was identified as the direct target of ESK981.
• PIKfyve inhibition mimicked ESK981's effects and enhanced immune checkpoint blockade response.

Conclusions:

• ESK981 exhibits anti-tumor effects in CRPC by inhibiting autophagy and targeting PIKfyve.
• ESK981 can 'hot' cold tumors, enhancing T cell infiltration and response to immunotherapy.
• Targeting PIKfyve with ESK981 represents a potential therapeutic strategy for advanced prostate cancer, alone or combined with immunotherapies.