Prostate cancer is among the most common malignancy in males. It is also the second leading cause of male cancer-related death in the Western world.  The PI3K pathway is associated with adverse outcomes of prostate cancer. In the Pten conditional knockout mouse model, selective inhibition of PI3Kβ shows no significant anti-tumor efficacy. However, selective inhibition of the PI3Kα isoform results in rebound activation of PI3Kβ in breast tumors with a PIK3CA activating mutation. Therefore, simultaneously inhibiting both PI3Kα and PI3Kβ activities may be a promising strategy for the treatment of cancers with PTEN loss or PI3K activation. BAY1082439 is an orally bioavailable, selective PI3K inhibitor. It shows equal potency against PI3Kα/β/δ isoforms. It has the potential for treating prostate cancer with PTEN-loss. By the way, LY294002 is also a broad-spectrum inhibitor of PI3K, with IC50s of 0.5, 0.57, and 0.97 μM for PI3Kα, PI3Kδ, and PI3Kβ, respectively.

In PTEN-null human prostate cancer cell lines (PC3 and LNCaP cells), BAY1082439 effectively inhibits cell growth. It blocks the G1/S cell cycle transition and induces apoptosis. In addition, BAY1082439 also inhibits mutated forms of PIK3CA. BAY1082439 is highly effective in inhibiting Pten-null prostate cancer growth. Meanwhile, BAY1082439 also inhibits mutated forms of PIK3CA.BAY1082439 is effective in preventing Pten-null prostate cancer progression in vivo. Moreover, it also prevents epithelial-mesenchymal transition (EMT) in the mutant Pten/Kras metastatic model. BAY1082439 further blocks B cell infiltration and lymphotoxin release.

In summary, BAY1082439 is a selective PI3Kα/β/δ inhibitor. It is highly effective in inhibiting Pten-null prostate cancer growth. Together, it is a new approach for the treatment of prostate cancer by targeting both tumor cells and tumor microenvironment with PI3Kα/β/δ inhibitor.


 Yongkang Zou, et al. Mol Cancer Ther. 2018 Oct;17(10):2091-2099.