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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.