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posted on 2023-11-20, 14:20 authored by Ailin Zhang, Nathan A. Lau, Alicia Wong, Lisha G. Brown, Ilsa M. Coleman, Navonil De Sarkar, Dapei Li, Diana C. DeLucia, Mark P. Labrecque, Holly M. Nguyen, Jennifer L. Conner, Ruth F. Dumpit, Lawrence D. True, Daniel W. Lin, Eva Corey, Joshi J. Alumkal, Peter S. Nelson, Colm Morrissey, John K. Lee Fimepinostat inhibits AR and Myc expression at the transcriptional level and suppresses full-length and variant expression. Plots showing RQ of AR (A) and Myc RNA (B) species based on qRT-PCR analysis of 22Rv1 and LNCaP95 cells treated with 1 µmol/L fimepinostat over a time course. Results are normalized to the 0 hour condition. Immunoblot analyses of cycloheximide chase experiments to evaluate AR (C) and Myc protein (D) stability after treatment of the 22Rv1 and LNCaP95 cell lines with 0.1% DMSO or 1 µmol/L fimepinostat. E, Immunoblot analyses for the 22Rv1 and LNCaP95 cell lines stably transduced with conditional Tet-on shRNA expression lentiviruses (targeting GFP as a control or different AR isoforms) and treated with doxycycline and/or 1 µmol/L fimepinostat for 24 hours. F, Immunoblot analyses of the CWR-R1 and CWR-R1-D567 cell lines after 24 hours of treatment with DMSO control or increasing doses of fimepinostat to determine the effects on expression of AR-FL and AR-Vs including ARv567es.
Funding
HHS | NIH | National Cancer Institute (NCI)
DOD | USA | MEDCOM | CDMRP | DOD Prostate Cancer Research Program (PCRP)
Prostate Cancer Foundation (PCF)
HHS | NIH | NIH Office of the Director (OD)
History
ARTICLE 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.
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.
