Co-Targeting of PI3K pathway with sphingolipid metabolism constitutes a promising therapeutic strategy against advanced stage prostate cancer

Abstract

Prostate cancer, PI3K, PTEN, Sphingolipid metabolism, S1PR, Isoform-Dependency, Metabolomics Prostate cancer is the second most diagnosed malignancy and the fifth leading cause of cancer driven death in men worldwide. The identification of driver mutations and genomic alterations, therefore, is crucially important to develop targeted strategies. Phosphatase and Tensin Homolog (PTEN) deletion has been shown among early and frequent alterations. Moreover, the PTEN loss of-function has been reported to be enriched in metastatic and high stage prostate cancers highlighting the role of PTEN deletion in metastatic growth. In this regard, our research group focuses on understanding the impact of PTEN loss in prostate epithelia from multiple aspects including metabolic reprogramming and oncogenic signaling. In this project, we revisit the influence of PTEN loss on PI3K Class IA isoform dependency shifts by using non-transformed prostate epithelial cells to model early PTEN deletion. Our findings show that PTEN loss results in a partial dependency shift to p110β and p110δ isoforms for growth and survival while p110α still remains as the predominant isoform. In parallel, we conduct targeted metabolomics to identify PTEN-regulated sphingolipid metabolites under the light of our previous work showing sphingolipid metabolism as a PTEN status regulated node. Our screening reveals that the ceramide levels are upregulated upon PTEN re-expression in all cell lines used in our screening whilst sphingosine-1-phosphate (S1P) metabolites are downregulated upon PTEN expression selectively in androgen deprivation therapy (ADT) resistant cells. We hypothesize that co-targeting PTEN loss-driven alterations synergistically inhibits the growth of high stage prostate cancers while sparing the PTEN-WT cells. To this end, we develop a combinatory treatment against p110β /p110δ and S1PR/SPHK1 to test our hypothesis. Our results conclude that co-inhibition of either p110β or p110δ along with S1P production or signaling acts synergistically to eliminate PTEN null and metastatic prostate cancers.