An estimated one in seven men will develop prostate cancer by the age of 60. The dependence of this form of cancer on androgen hormone signalling for growth and development distinguishes it from other tissue types. New androgen targeted treatments have improved prostate cancer outcomes. However, some patients develop resistance to these therapies. Despite great scientific efforts, the whole network of biochemical changes that occur during prostate cancer progression has yet to be characterized. 

The assumption of Joanna Triscott and her colleagues was that PI5P4Ks (Phosphatidylinositol 5-phosphate 4-kinases), a family of relatively understudied metabolic enzymes, plays an important role in prostate cancer biology. Therefore, they aimed to determine whether PI5P4Kα influences the ability of cancer cells to adapt to treatment stress, which might lead to the discovery of a potential vulnerability in cancer survival. To test whether PI5P4Kα has a relationship with androgen receptor (AR) hormone signalling, they queried patient datasets and used cell culture models to experimentally determine the impact of down regulation of PI5P4Kα. Additionally, they generated a prostate-specific PI5P4Kα-targeted mouse model to assess fundamental prostate biology. 

The results show that expression of PI5P4Kα is increased in advanced prostate cancer cells and based on the mouse model, is localized to the lysosome. Data from in vivo and in vitro experiments further demonstrate that prostate cancer cells dramatically increase the volume of lysosomes under conditions of androgen receptor inhibition, and that PI5P4Kα may interact with androgen receptor signalling through a key pathway in cancer biology called mTORC1. Finally, the scientists could show in vitro that depletion of PI5P4Kα makes cancer cells less viable. 

Joanna Triscott and her team shed light on the role of the lesser known lipid regulator PI5P4Kα in prostate cancer and its relationship with androgen hormone signalling, which promotes cancer cell survival. The study showed the importance of lipid regulation during metabolic stress adaptation in prostate cancer, particularly under androgen deprivation. This remarkable work suggests that targeting PI5P4Kα could disrupt the metabolic adaptation of prostate cancer as it progresses. This could make the enzyme a potential target for the development of new drugs against prostate cancer.

PI5P4Kα supports prostate cancer metabolism and exposes a survival vulnerability during androgen receptor inhibition. Joanna Triscott, Matthias Reist, Lukas Küng, Francielle C. Moselle, Marika Lehner, John Gallon, Archna Ravi, Gurpreet K. Arora, Simone de Brot, Mark Lundquist, Hector Gallart-Ayala, Julijana Ivanisevic, Salvatore Piscuoglio, Lewis C. Cantley, Brooke M. Emerling, Mark A. Rubin. Sci Adv. 2023 Feb 3;9(5):eade8641