Metastatic castration-resistant prostate cancer (mCRPC) is an aggressive malignancy with poor outcomes. To investigate novel therapeutic strategies, we characterized three new metastatic prostate cancer PDTX models and developed 3D spheroids from each to investigate molecular targeted therapy combinations including CDK4/6 inhibitors (CDK4/6i) with AKT inhibitors (ATKi). Metastatic prostate cancer tissue was collected and three PDTX models were established and characterized using WES. PDTX 3-D spheroids were developed from these three PDTXs to show resistance patterns and test novel molecular targeted therapies. CDK4/6i's were combined with AKTi's to assess synergistic antitumor response to prove our hypothesis that blockade of AKT overcomes drug resistance to CDK4/6 inhibitor. This combination was evaluated in PDTX 3-D spheroids and in vivo experiments with responses measured by tumor volumes, PSA and Ga-68 PSMA-11 PET-CT imaging. We demonstrated CDK4/6i's with AKTi's possess synergistic antitumor activity in three mCRPC PDTX models. These models have multiple unique pathogenic and deleterious genomic alterations with resistance to single agent CDK4/6i's. Despite this, combination therapy with AKTi's was able to overcome resistance mechanisms. The IHC and Western blot analysis confirmed on target effects, while tumor volume, serum PSA ELISA, and radionuclide imaging demonstrated response to therapy with statistically significant SUV differences seen with Ga-68 PSMA-11 PET-CT. These preclinical data demonstrating antitumor synergy by overcoming single agent CDK 4/6i as well as AKTi drug resistance provide the rational for a clinical trial combining a CDK4/6i with an AKTi in mCRPC patients whose tumor expresses wild type RB1.
Molecular cancer therapeutics. 2024 Mar 06 [Epub ahead of print]
Adam M Kase, Justyna Gleba, James L Miller, Erin Miller, Joachim Petit, Michael T Barrett, Yumei Zhou, Ephraim E Parent, Hancheng Cai, Joshua A Knight, Jacob Orme, Jordan Reynolds, William F Durham, Thomas M Metz, Nathalie Meurice, Brandy Edenfield, Aylin Alasonyalilar Demirer, Ahmet Bilgili, Peyton G Hickman, Matthew L Pawlush, Laura Marlow, Daniel P Wickland, Winston Tan, John A Copland
Mayo Clinic, Jacksonville, FL, United States., Mayo Clinic, Scottsdale, Arizona, United States., Mayo Clinic, Scottsdale, AZ, United States., Mayo Clinic, Rochester, MN, United States., Charles River Discovery Services, Morrisville, NC, United States., Charles River Discovery Services, Freiburg, Baden-Württemberg, Germany., Mayo Clinic, Jacksonville, Florida, United States., Mayo Clinic, Jacksonville, United States.