Prostate cancer (PCa) accounts for approximately 26,730 deaths each year in the United States. The tremendous heterogeneity observed among prostate cancers contributes to the enormous clinical challenge. Among these tumors, variant Neuroendocrine Prostate Cancers (NEPC) account for up to a third of prostate cancer-related deaths. These tumors are enriched with cancer cells with stem-cell properties (CSCs). Prostate CSCs lack the expression of androgen-receptor (AR), and are hence resistant to AR inhibition. In addition, CSCs are capable of sustaining tumor relapse and metastasis. We previously demonstrated that aberrant induction of epithelial-mesenchymal transition (EMT) in differentiated prostate epithelial cells could result in the activation of CSC features, including ADT resistance and NEPC attributes. Using multiple prostate cancer cell lines as well as patient-derived xenograft samples, we demonstrated a reciprocal relationship between the EMT/CSC phenotype and expression of AR, and also observed a vital role for the central EMT regulator FOXC2 (Forkhead transcription factor C2) in the generation/maintenance of AR-negative CSCs, which are in turn responsible for the formation of NEPCs. We therefore sought to identify conserved EMT-signaling pathways necessary for EMT and neuroendocrine trans-differentiation in PCa cells, and investigate if targeting EMT-promoting pathways renders CSC-enriched PCa cells sensitive to ADT. We demonstrate that FOXC2 is a direct target of p38MAPK (a pleiotropic kinase), and that the p38-FOXC2 signaling cascade is indispensable for NEPC attributes and associated stem-cell functions. Targeting the p38 pathway using a systemic small-molecule inhibitor in animal models in vivo induced epithelial differentiation in NEPCs and indeed rendered them sensitive to androgen-deprivation therapy using enzalutamide, via loss of FOXC2 function. This study therefore highlights a novel (and targetable) signaling pathway that fosters CSC-associated drug resistance in NEPC, and a pioneering treatment potential for patients with NEPC. Acknowledgments: We thank Dr. Nupam Mahajan (Moffitt Cancer Center, University of South Florida, Tampa), Dr. Ignacio Wistuba, Dr. Jaime Rodriguez-Canales, Dr. Sue-Hwa Lin (Department of Translational Molecular Pathology, UT MDACC, Houston) and Dr. Dean Tang (Department of Molecular Carcinogenesis, MDACC, Smithville) for their contributions. We thank the UTMDACC Prostate Cancer SPORE for financial support (RS, SM).

Citation Format: Rama Soundararajan, Anurag Paranjape, Robiya Joseph, Neeraja Bhangre, Ana Aparicio, Sankar Maity, Christopher Logothetis, Jeffrey Chang, Sendurai Mani. Modulating a cancer stem cell-specific signaling pathway to reverse the course of neuroendocrine prostate cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A065.