Concurrent Targeting of HDAC and PI3K to Overcome Phenotypic Heterogeneity of Castration-resistant and Neuroendocrine Prostate Cancers
Abstract
Castration-resistant prostate cancer (CRPC) consists of multiple phenotypic subtypes including androgen receptor (AR)-active prostate cancer (ARPC) and neuroendocrine prostate cancer (NEPC). Tumor cells with these phenotypes can coexist between metastases within a patient and within an individual tumor. Treatments that are effective across CRPC subtypes are currently lacking. Histone deacetylation is crucial for the regulation of chromatin structure and maintenance of cancer cell state and activation of the PI3K/AKT/mTOR signaling cascade is a tumor growth–promoting pathway. We therefore investigated combined targeting of histone deacetylase (HDAC) and PI3K using a rationally designed dual inhibitor, fimepinostat, in CRPC subtypes in vitro and in vivo. Dual HDAC1/2 and PI3K/AKT pathway inhibition by fimepinostat led to robust tumor growth inhibition in both ARPC and NEPC models including cell line– and patient-derived xenografts. HDAC1/2 inhibition combined with PI3K/AKT inhibition was more effective than targeting each pathway alone, producing growth inhibitory effects through cell-cycle inhibition and apoptosis. Molecular profiling revealed on-target effects of combined HDAC1/2 and PI3K/AKT inhibition independent of tumor phenotype. Fimepinostat therapy was also associated with the suppression of lineage transcription factors including AR in ARPC and Achaete-scute homolog 1 (ASCL1) in NEPC. Together, these results indicate that fimepinostat represents a novel therapeutic that may be effective against both ARPC and NEPC through CRPC subtype-dependent and -independent mechanisms.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Nov 20, 2023
- Source ID
- 10.1158/2767-9764.crc-23-0250
Entities
People
- Ailin Zhang
- Alicia Wong
- Colm Morrissey
- Daniel W Lin
- Dapei Li
- Diana C. DeLucia
- Eva Corey
- Holly M. Nguyen
- Ilsa M. Coleman
- Jennifer L. Conner
- John K Lee
- Joshi J Alumkal
- Lawrence D. True
- Lisha G. Brown
- Mark P Labrecque
- Nathan A. Lau
- Navonil De Sarkar
- Peter S Nelson
- Ruth F. Dumpit
Organizations
- Fred Hutchinson Cancer Center
- Medical College of Wisconsin
- National Cancer Institute
- Office of the Director
- Prostate Cancer Foundation
- University of Michigan
- University of Washington