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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 Transcriptional changes associated with fimepinostat treatment are largely conserved between CRPC and NEPC. A, Venn diagrams showing overlapping upregulated and downregulated genes in the 22Rv1 and LNCaP95 cell lines after treatment with 1 µmol/L fimepinostat relative to treatment with 0.1% DMSO for 24 hours. B, Plots showing commonly enriched (top, yellow bars) and de-enriched (bottom, blue bars) MSigDB hallmark gene sets from GSEA of overlapping genes in A. C, Gene expression heat map of 22Rv1 and LNCaP95 cells treated with DMSO or increasing doses of fimepinostat for 24 hours. Select genes including Myc, AR, AR targets, NE markers, and EMT markers are shown. D, Venn diagrams showing overlapping upregulated and downregulated genes in the NCI-H660 and MSKCC EF1 cell lines after treatment with 1 µmol/L fimepinostat relative to treatment with 0.1% DMSO for 24 hours. E, Plots showing commonly enriched (top, yellow bars) and de-enriched (bottom, blue bars) MSigDB hallmark gene sets from GSEA of overlapping genes in D. F, Gene expression heat map of NCI-H660 or MSKCC EF1 cells treated with DMSO or increasing doses of fimepinostat for 24 hours. Select genes including Myc paralogs and NE transcription factors are shown. G, Plot showing the overall changes in gene expression of transcription factors after treatment with 1 µmol/L fimepinostat relative to treatment with 0.1% DMSO for 24 hours. Select highly enriched and de-enriched transcription factors are labeled.
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.
