Delineating how PIK3CA mutation and PTEN deletion contribute to prostate cancer
Session type: Poster / e-Poster / Silent Theatre session
The phosphatidylinositol-3-kinase (PI3K) pathway is frequently activated in prostate cancer to promote tumour growth, and is linked to androgen-deprivation therapy (ADT) resistance that leads to lethal castrate-resistant prostate cancer (CRPC). A key clinical challenge faced, is how to effectively target the PI3K cascade to treat prostate cancer and aid patient care. Previous work in the lab has identified that Pten loss and Pik3ca activation, which frequently drive PI3K signalling in patients with prostate cancer, cause distinct prostate cancer pathologies and can cooperate to accelerate tumorigenesis and CRPC transition in vivo. These data suggest that different PI3K genetic drivers mediate distinct signalling events that could provide new avenues for therapeutic intervention and/or patient stratification.
To delineate the mode of action of oncogenic Pik3ca (Pik3ca+/H1047R) and Pten loss (Ptenfl/fl) during prostate cancer, RNA was isolated from Pik3ca-activated and Pten-deleted murine prostate tumours (intact and post-castration) and RNA-Sequencing performed (n = 5/cohort). Following data processing, Ensemble gene set enrichment pathway analysis (EGSEA) was performed.
In the intact setting, we report a significant upregulation of NK-ƙB and MYC signalling in Pten-deleted prostate cancer relative to Pik3ca-activated prostate tumours. In the castrate setting, de novo CRPC tumours deficient for Pten and harbouring a Pik3ca-activating mutation displayed reduced apoptosis/senescence and reduced proteosomal interactions compared to acquired CRPC Pten-deleted tumours.
These findings support the concept that different genetic drivers of the PI3K cascade mediate independent signalling events that contribute to prostate cancer progression. Further work is required to verify the functional importance of the signalling events identified, and to establish if targeting them in conjunction with PI3K pathway-targeted therapy is more efficacious than monotherapy.