Dual targeting of the androgen receptor and PI3K/AKT/mTOR pathways in prostate cancer models improves antitumor efficacy and promotes cell apoptosis
Prostate cancer remains one of the most common malignancies in men, with treatment resistance continuing to be a major challenge. When detected early, five-year survival rates are very high; however, if the tumor has spread, prostate cancer presents a much more challenging problem. Initially most prostate cancers respond when treated with compounds that block androgen receptor signaling, but eventually tumors progress.
Signaling through the PI3 kinase/ATK/mTOR pathway has been reported for advanced prostate cancer, suggesting that this signaling pathway might make a good target for improved therapeutics. Research published in Molecular Oncology presents a novel strategy for therapeutic development: targeting both the androgen receptor (AR) and PI3K/AKT/mTOR pathways simultaneously. By combining the AR inhibitor darolutamide with PI3 kinase inhibitors, researchers observed enhanced tumor suppression and increased apoptosis. This work potentially offers a new direction for treatment-resistant prostate cancer, although on-target toxicity of PI3 kinase/ATK/mTOR pathway inhibitors presents a challenge.
This study leveraged Promega advanced bioluminescent and target engagement assays to evaluate drug efficacy, apoptosis, and kinase activity in prostate cancer models and the cross-disciplinary expertise of scientists from Bayer AG, Nuvisan ICB GmbH, the University of Washington, and Promega Corporation.
Key Promega technologies used include:
- NanoBRET™ Target Engagement Assay: Used to determine the potency of the intracellular inhibitors of PI3 kinase.
- Caspase-Glo® 3/7 Assay: Used to detect apoptosis in androgen-dependent prostate cancer cells treated with PI3 kinase/AKT/mTOR pathway inhibitors alone or in combination with darolutamide (an AR inhibitor), revealing increased apoptosis over the singly-treated cells.
- CellTiter-Glo Luminescent Cell Viability Assay. Used to develop dose-response curves and IC50 information of the inhibitors tested.
