Presentation Authors: Zhenghong Li*, Carrie Qi Sun, Rebecca Arnold, John A Petros, Carlos S Moreno, Atlanta, GA
Introduction: Androgen receptor (AR) signaling is a distinctive feature of prostate cancer (PCa) and represents a major therapeutic target for treating metastatic prostate cancer (mPCa). Thus, androgen deprivation therapy (ADT) is a first-line treatment for mPCa. Although initially highly effective as a treatment for mPC, ADT is characterized by the frequent emergence of resistance, a disease state termed castration-resistant prostate cancer (CRPC) and is generally incurable after progression to metastatic disease. Therefore, understanding the mechanisms underlying CRPC and subsequent progression to metastatic disease is critical. In our previous study, which was mainly focused on how transcriptional networks change in response to ADT and lead to metastasis, we analyzed matched pre-ADT and post-ADT tissue samples via RNAseq analysis of 40 formalin-fixed paraffin-embedded (FFPE) patient-matched pre-ADT biopsy (Bx) and post-ADT radical prostatectomy (RP) prostate cancer samples. We observed strong upregulation of components of the MAPK pathway including FOS, FOSB, and JUN, as well as downstream targets of MAPK signaling. These data suggest that ADT may induce a compensatory increase in MAPK signaling in response to the decrease in androgen signaling. Thus, we hypothesize that combination therapies targeting AR and the MAPK pathway may synergistically kill prostate cancer cells and prevent recurrence and progression to CRPC.
Methods: Cell Viability and Cytotoxicity Assays, MTT assays, Transwell Cell Migration and Invasion assays were used to evaluate the viability, cytotoxicity, proliferation, migration and invasion abilities of LNCaP cell after treated with Enzalutamide and MEK inhibitors PD0325901 and GSK1120212, ERK1/2 inhibitor GDC-0994, and the JNK inhibitor AS602801 alone and in combination with enzalutamide in androgen-sensitive LNCaP and MDA-PCa-2b cells. Western blot analysis was conducted to detect the expression of androgen-receptor(AR) and prostate-specific antigen(PSA), p-Erk/Erk, p-JNK/JNK.
Results: Cell viability assays indicated that enzalutamide combined with MEK and JNK inhibitors synergistically killed LNCaP, and decreased migration and invasion of LNCaP cell more than any of the drugs alone.
Conclusions: combination therapy targeting AR and MEK and/or JNK signal pathways may be an effective treatment for recurrent prostate cancer. We are currently investigating the most promising combinations of enzalutamide with JNK inhibitors for anti-tumorigenic effects in vivo using a mouse xenograft model.
Source of Funding: These studies were supported in part by the Dunwoody Golf Club Prostate Cancer Research Award, a philanthropic award provided by the Winship Invest$ Prostate Cancer Research Pilot Grant Program.