Neuroendocrine differentiation post anti-androgenic therapy: Role of Tribbles 2

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Anti-androgenic therapy is the mainstay for both primary and disseminated forms of prostate cancer. FDA- approved enzalutamide (Xtandi) is at the forefront of anti-androgens with superior patient profile and is the one most prescribed. However, enzalutamide resistant prostate cancer (ERPC) invariably develops, which is incurable and responsible for most of the prostate cancer-related deaths, underscoring that management of ERPC is an unmet and urgent medical need. Development of an effective therapy against ERPC is suffering from lack of proper understanding about critical molecular targets to effectively kill ERPC cells. To identify potential new targets, we developed an ERPC model which mimics the clinical conditions in patients undergoing standard enzalutamide therapy. We treated androgen-sensitive prostate cancer cells with enzalutamide in long- term culture to generate cell lines (LNCaP-ENR, PCa-2B-ENR) which are no longer sensitive to clinically relevant doses of enzalutamide. Comprehensive gene expression analysis revealed that the ERPC cells overexpress Tribbles 2 (Trib2), a member of the tribbles pseudokinase family. Overexpression of Trib2 was also found in PDX and patient prostate tumors after enzalutamide treatment. Forced overexpression Trib2 results in enhanced prostate cancer cell growth and resistance to enzalutamide, apalutamide, darolutamide and abiraterone. Inhibition of Trib2 re-sensitizes resistant cells to enzalutamide and decreases their viability, indicating a possible direct link between Trib2 and development of enzalutamide resistance. Interestingly, Trib2 downregulates Rb1 and p53, while induces the neuronal transcription factors (N-Myc, BRN2) and the neuroendocrine (NE) markers (Chromogranin A, Neuron-specific enolase and Synaptophysin). Inhibition of N-Myc or BRN2 re-sensitizes resistant cells to enzalutamide. These findings suggest that Trib2 drives cellular trans-differentiation from luminal to NE phenotype to pose resistance to anti-androgens. Thus, Trib2 emerges as a novel, promising molecular target for therapy of ERPC-NE. However, the mechanism and role of Trib2 in NE differentiation needs to be determined using appropriate in vitro and in vivo models. Thus, this proposal has been designed which will characterize how Trib2 induces NE differentiation (Aim 1), determine the impact of Trib2 inhibition in enhanced ERPC tumor growth and distant metastasis (Aim 2), and test the impact of Trib2 gene-targeting on prostate tumor progression and NE differentiation using transgenic Trib2 knockout mouse models (Aim 3). Accomplishing these goals will establish Trib2 as a molecular driver for treatment-induced NE differentiation and will help develop a new targeted therapeutic strategy for enzalutamide resistant, NE type, lethal prostate cancer.