Neuropilin-2, A Potential Target Against Neuroendocrine Like Therapy Resistant Prostate Cancer.

Abstract Background: Prostate cancer (PCa) patient management is becoming increasingly challenging owing to the emergence of advanced therapy-resistant PCa. Published reports from our laboratory demonstrated that neuropilin-2 (NRP2), a non-tyrosine kinase transmembrane receptor, is associated with therapy resistance in aggressive PCa. Such advanced PCa is often associated with diverse genetic changes that complicate the therapeutic interventions. One example is the loss of tumor suppressor gene TP53 along with RB1 to develop therapy resistant neuroendocrine (NE)-like PCa that evades the standard androgen depletion therapy (ADT) and is resistant to first-line chemotherapy. Our results indicate that loss of TP53 and RB1 is associated with significantly increased expression of NRP2. Significance of the problem: Switch to NE-like lineage has been found to be associated with resistance to androgen receptor (AR) targeted therapy as well as chemotherapy. Patients with NE-like PCa show poor prognosis owing to the heterogeneous feature of the tumors and unavailability of effective therapy against this type of cancer. Therefore, identification of potential molecular target(s) is necessary to combat this disease. Objective: The objective of this study is to comprehend the underlying molecular mechanism/s of increased NRP2 expression in PCa, and whether targeting NRP2 would be effective against therapy resistant NE-like PCa, especially in combination with first-line chemotherapeutic agents. Study design: Current study was performed to test the NRP2 status in NE-like PCa cells and to understand if NRP2 is associated with the therapy resistance in this type of aggressive cancer. Moreover, efficacy of NRP2 depletion to sensitize the cancer cells to the chemotherapeutic agents used clinically was evaluated. A stable cell line model of NE-like PCa was developed and characterized by knocking down TP53 and RB1 genes in castration resistant prostate cancer (CRPC) cells. The resistance of the cells against the clinically used chemotherapy was investigated. In addition, efficacy of the chemotherapeutic agents following NRP2 knockdown was evaluated in in-vitro and in-vivo models. For in-vivo studies, PCa bone metastatic mouse model was developed in our laboratory and the effect of the depletion of NRP2 in combination with chemotherapeutic agent was evaluated. Results: NRP2 was significantly expressed in the NE-like PCa cells and knockdown of NRP2 sensitized the originally resistant NE-like cells to chemotherapeutic drugs. Tumor burden was also reduced in the bone metastatic mouse model upon NRP2 depletion when given in combination with chemotherapy. Conclusion: Therefore, targeting NRP2 can be an effective therapeutic strategy to combat highly aggressive and therapy resistant NE-like PCa. Citation Format: Ridwan Islam, Navatha Polavaram, Zhengdong Hong, Sreyashi Bhattacharya, Sanika Bodas, Benjamin Teply, Michael Muders, Kaustubh Datta, Samikshan Dutta. Neuropilin-2, a potential target against neuroendocrine like therapy resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1422.