7P HIFA1 inhibition as a therapeutic strategy for overcoming castration resistance in PTEN-deficient prostate cancer

Abstract

Prostate cancer (PCa) is the second most commonly diagnosed neoplasia in men worldwide. The growth of prostate cancer cells is initially dependent of the activity of the androgen receptor (AR) and AR is the target of first-line prostate cancer systemic treatments. The benefit of adding neoadjuvant and adjuvant androgen deprivation therapy is well established for men with high-risk localized and advanced disease. However, some patients develop castration resistant prostate cancer, for which curative options are limited. PTEN is the most often tumor suppressor gene mutated in PCa patients. Hypoxic regions have been found in prostate adenocarcinoma, and elevated expression of hypoxia markers, including HIF1a (hypoxia-inducible factor 1A), have been shown to identify PCa patients with elevated risk of biochemical recurrence. Prostate tumors of sham-operated and castrated Pten(i)pe-/- mice, which have a prostatic luminal cell-specific inactivation of PTEN after puberty, were analyzed by droplet-based single cell-RNA sequencing. Moreover, the impact of genetic and pharmacological Hif1a inhibition was determined in castrated Pten(i)pe-/- mice by histological analyses. To gain insights on pathways driving androgen-independence in prostate tumor, we analyzed Pten(i)pe-/- mice which develop tumors that are resistant to castration. Droplet based single cell-RNA sequencing of 17265 cells from dissociated tumors of castrated and sham-operated Pten(i)pe-/- mice revealed that androgen deprivation enhances hypoxia signaling in luminal cells. Importantly, this is accompanied by the emergence of an immune-cell-related gene signature in luminal cells of castrated mice, indicating that activation of hypoxic signaling and induction of cellular plasticity are involved in castration resistance. Importantly, genetic ablation of Hif1a in prostatic tumors sensitizes them to castration, and pharmacological inhibition of Hif1a together with androgen deprivation leads to durable anti-tumoral response. Androgen deprivation in combination with HIF1 signaling inhibition is a promising therapeutic strategy for overcoming castration resistance in PTEN-deficient prostatic tumors.