Much of the morbidity and mortality due to prostate cancer happen because of castration-resistant prostate cancer (CRPC) which invariably develops after anti-androgenic therapy. FDA-approved enzalutamide is commonly prescribed for CRPC which works by blocking androgen receptor function. However, even after initial good response, enzalutamide-resistant prostate cancer (ERPC) develops which eventually leads to widespread metastasis. Management of ERPC is extremely difficult because available therapeutic regimen cannot effectively kill and eliminate ERPC cells. Though the mechanism behind enzalutamide-resistance is not properly understood, over-activation of c-Myc has been found to be a common event which plays an important role in the maintenance and progression of ERPC phenotype. However, direct-targeting of c-Myc poses special problem because of its non-enzymatic nature and certain amount of c-Myc activity is needed by non-cancer cells as well. Thus, c-Myc has emerged as an elusive target which needs to be managed by novel agents and strategies in a cancerspecific way. We investigated the effects of pharmacological and genetic inhibition of 5-lipoxygenase (5-Lox) on cell proliferation, apoptosis and invasive potential of enzalutamide-resistant prostate cancer cells. Transcriptional activity of c-Myc was analyzed by DNA-binding, luciferase-assays, and expression of c-Myc-target genes. We found that 5-Lox regulates c-Myc signaling in enzalutamide-resistant prostate cancer cells and inhibition of 5-Lox by Quiflapon/MK591 or shRNA interrupts oncogenic c-Myc signaling and kills ERPC cells by triggering caspase-mediated apoptosis. Interestingly, MK591 does not affect normal, non-cancer cells in the same experimental conditions. Our findings indicate that inhibition of 5-Lox may emerge as a promising new approach to effectively kill ERPC cells sparing normal cells and suggest that development of a long-term curative therapy of prostate cancer may be possible by killing and eliminating ERPC cells with suitable 5-Lox-inhibitors. Prostate cancer is the most prevalent form of malignancy and a leading cause of cancer-related deaths in American men taking thousands of lives every year 1. Much of the morbidity and mortality due to prostate cancer is caused by castration-resistant prostate cancer (CRPC), which invariably develops after initial good response with androgen-deprivation therapies (ADT). Enzalutamide, an FDA-approved inhibitor of androgen receptor function, is commonly prescribed to treat castration-resistant prostate cancer 2-5. While Enzalutamide improves survival and quality of life of patients with castrate-resistant disease, which highlights the benefit of targeting the AR axis in CRPC, enzalutamide-resistant prostate cancer (ERPC) almost always develops which leads to widespread metastatic disease eventually bringing demise to prostate cancer patients 4-6. ERPC is not curable because currently available therapeutic regimen cannot effectively kill and eliminate ERPC cells. Thus, ERPC is considered

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Background: Enzalutamide is an FDA-approved drug commonly prescribed for advanced prostate cancer. Enzalutamide slows down prostate tumor growth but resistant disease invariably develops which is incurable primarily because currently available therapies cannot effectively kill enzalutamide-resistant prostate cancer cells. Mechanism(s) behind development of enzalutamide-resistance is not properly understood, though overactivation of c-Myc has been found to be a common event which plays an important role in the maintenance and progression of ERPC phenotype. However, direct-targeting of c-Myc poses special problem because of its non-enzymatic nature and certain amount of c-Myc activity is needed by non-cancer cells as well. Thus, c-Myc has emerged as an elusive target which needs to be managed by novel agents and strategies in a cancer-specific way for better control of ERPC. Methods: We addressed this problem by treating ERPC cells with a variety of cell survival and apoptosis-regulating agents followed by measurement of cell viability, and by analysis of the mRNA and protein levels of c-Myc. Gene expression was analyzed by Illumina Hi-Seq whole genome gene-expression array. Expression of c-Myc was confirmed by RT-PCR and Western blot. Apoptosis was measured by annexin-V binding, PARP-cleavage, and by detecting degradation of chromatin-DNA to nucleosomes. Transcriptional activity of c-Myc was analyzed by nuclear accumulation, DNA-binding, luciferase-reporter assays and expression of c-Myc-target genes. Results: We found that MK591, a leukotriene biosynthesis inhibitor, dramatically downregulates c-Myc in ERPC cells as revealed by RT-PCR, and Western blot as well as by the reduction in nuclear-accumulation and DNA-binding activities of c-Myc. Treatment with MK591 decreased the Myc-driven E-box-luciferase reporter activity, and substantially reduced the expression of c-Myc target genes (Cyclin D1, CDK4, survivin, Aurora kinase). Moreover, MK591 effectively blocked in vitro invasion and soft-agar colony-formation by ERPC cells. Interestingly, while MK591 strongly inhibits c-Myc function and kills ERPC cells via caspase-mediated apoptosis, it does not inhibit the basal c-Myc function or the viability of non-cancer cells, such as human foreskin fibroblasts (HFF). Conclusion: Our findings indicate that the expression and oncogenic-function of c-Myc in ERPC cells are severely downregulated by MK591, and suggest that MK591 may turn out to be a suitable new agent to treat advanced, aggressive prostate cancers which are resistant to enzalutamide therapy. Citation Format: Jitender Monga, Ajay Bharathan, Dhatchayini Subramani, Jagadananda Ghosh. MK591 (Quiflapon) downregulates c-Myc oncogenic signaling and induces apoptosis in enzalutamide-resistant prostate cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1275.

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