Faculty Collaboration Database

Concurrent Targeting of HDAC and PI3K to Overcome Phenotypic Heterogeneity of Castration-resistant and Neuroendocrine Prostate Cancers. Cancer Res Commun 2023 Nov 20;3(11):2358-2374

Date

10/12/2023

Pubmed ID

37823778

Pubmed Central ID

PMC10658857

DOI

10.1158/2767-9764.CRC-23-0250

Scopus ID

2-s2.0-85182280871 (requires institutional sign-in at Scopus site)   19 Citations

Abstract

UNLABELLED: 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.

SIGNIFICANCE: CRPC is a heterogeneous disease constituting multiple phenotypic subtypes that often co-occur within tumors or across metastases in patients. Existing targeted therapies for CRPC do not take this into account. Here we show that fimepinostat, a dual HDAC1/2 and PI3K/AKT inhibitor investigated clinically in other cancer types but not prostate cancer, may overcome this heterogeneity by effectively inhibiting both ARPC and NEPC subtypes of CRPC.

Author List

Zhang A, Lau NA, Wong A, Brown LG, Coleman IM, De Sarkar N, Li D, DeLucia DC, Labrecque MP, Nguyen HM, Conner JL, Dumpit RF, True LD, Lin DW, Corey E, Alumkal JJ, Nelson PS, Morrissey C, Lee JK

Author

Navonil De Sarkar PhD Assistant Professor in the Pathology and Laboratory Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Castration
Histone Deacetylases
Humans
Male
Morpholines
Phenotype
Phosphatidylinositol 3-Kinases
Prostatic Neoplasms, Castration-Resistant
Proto-Oncogene Proteins c-akt
Pyrimidines
Sulfur Compounds