Tribbles 2 pseudokinase confers enzalutamide resistance in prostate cancer by promoting lineage plasticity

Jitender Monga,Indra Adrianto,Craig Rogers,Shirish Gadgeel,Dhananjay Chitale,Joshi J Alumkal,Himisha Beltran,Amina Zoubeidi,Jagadananda Ghosh

doi:10.1016/j.jbc.2021.101556

Abstract

Enzalutamide, a second-generation antiandrogen, is commonly prescribed for the therapy of advanced prostate cancer, but enzalutamide-resistant, lethal, or incurable disease invariably develops. To understand the molecular mechanism(s) behind enzalutamide resistance, here, we comprehensively analyzed a range of prostate tumors and clinically relevant models by gene expression array, immunohistochemistry, and Western blot, which revealed that enzalutamide-resistant prostate cancer cells and tumors overexpress the pseudokinase, Tribbles 2 (TRIB2). Inhibition of TRIB2 decreases the viability of enzalutamide-resistant prostate cancer cells, suggesting a critical role of TRIB2 in these cells. Moreover, the overexpression of TRIB2 confers resistance in prostate cancer cells to clinically relevant doses of enzalutamide, and this resistance is lost upon inhibition of TRIB2. Interestingly, we found that TRIB2 downregulates the luminal markers androgen receptor and cytokeratin 8 in prostate cancer cells but upregulates the neuronal transcription factor BRN2 (Brain-2) and the stemness factor SOX2 (SRY-box 2) to induce neuroendocrine characteristics. Finally, we show that inhibition of either TRIB2 or its downstream targets, BRN2 or SOX2, resensitizes resistant prostate cancer cells to enzalutamide. Thus, TRIB2 emerges as a potential new regulator of transdifferentiation that confers enzalutamide resistance in prostate cancer cells via a mechanism involving increased cellular plasticity and lineage switching.

Highlights

Enzalutamide, an inhibitor of androgen receptor function, is a popular drug commonly prescribed to treat advanced prostate cancer, but resistant prostate cancer eventually develops which grow aggressively, leading to widespread metastatic disease and ends up with a lethal outcome [1,2,3]
RT-PCR and Western blot we found that enzalutamide resistant prostate cancer cells overexpress Tribbles 2, a member of the Tribbles pseudokinase family (TRIB1-3)
Inhibition of either Tribbles 2 (TRIB2) or its targets (BRN2 or SOX2) re-sensitizes resistant cells to enzalutamide. These findings indicate that TRIB2 is a new biomarker for NE type prostate cancer and suggest that TRIB2 may contribute to enzalutamide resistance in prostate cancer cells, at least in part, by promoting lineage plasticity and phenotype switching

Summary

Introduction

Enzalutamide, an inhibitor of androgen receptor function, is a popular drug commonly prescribed to treat advanced prostate cancer, but resistant prostate cancer eventually develops which grow aggressively, leading to widespread metastatic disease and ends up with a lethal outcome [1,2,3]. Current molecular understanding suggests that in addition to AR reactivation by mutation or splice variants, manifestation of enzalutamide resistance can be the result of overgrowth of cells that are developed in the tumor by lineage switching which may be triggered by drug-induced repression or loss of the AR-signaling [7,8,9]. Though the continued growth and metastasis of the heavily enzalutamide-treated prostate tumors can be driven by non-androgenic signaling, molecular underpinnings of critical targetable mechanisms in treatment-emergent NE type prostate cancer cells are yet to be fully characterized

Methods

Results

Conclusion