Blocking PIKfyve Promotes Autophagy in Prostate Cancer Cells

Researchers at the University of Michigan Rogel Cancer Center report that a protein called PIKfyve impacts multiple processes involved in metabolism and cell death and that blocking it is key to making immunotherapy work in prostate cancer. Their findings were published in Nature Cancer. 

The team began their experiments by screening a library of 167 inhibitors against prostate cancer cells. They found one, ESK981, had the most impact. ESK981 is a class of drugs called multi-tyrosine kinase inhibitors, which are designed to hit multiple targets. From there, they continued to untangle the web to discover multiple levels of cellular processes that were preventing the immune system from mounting a response.

In cell lines and mice with metastatic castration-resistant prostate cancer, the scientists found that ESK981 inhibited tumor growth. “The response was intriguing, but we wanted to understand the mechanism at play with ESK981 in prostate cancer cells,” senior author Arul Chinnaiyan says. The authors surprisingly found that ESK981 was a potent inhibitor of autophagy in tumor cells. This caused the cancer cells to produce a protein called CXCL10, which led to the recruitment of immune T cells to the tumor. Ultimately, they traced it back to PIKfyve, a type of protein called a lipid kinase. The authors discovered that ESK981 directly targets PIKfyve, affecting these multiple processes involved in metabolism and cell death.

The researchers confirmed this by knocking down PIKfyve in cell lines and mice. They saw the same processes occur: tumors stopped growing, autophagy was controlled and more T cells were recruited to the tumor. When they added an immune checkpoint inhibitor to the PIKfyve knockdown, the impact was even greater, significantly reducing tumors.