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

Abstract

Second-generation anti-androgen, such as enzalutamide (Xtandi), is commonly prescribed for prostate cancer therapy, but enzalutamide-resistant, lethally incurable disease invariably develops. To understand the molecular basis of enzalutamide resistance, we comprehensively analyzed prostate tumors and clinically relevant models. These studies revealed that enzalutamide resistant prostate cancer cells overexpress Tribbles 2 (Trib2), a pseudokinase. Expression of Trib2 is negatively regulated by androgen receptor signaling. Overexpression of Trib2 makes prostate cancer cells completely resistant to clinically relevant doses of enzalutamide. Trib2 downregulates expression of luminal markers but upregulates the neuronal transcription factor, BRN2, and the stemness factor, SOX2, to induce neuroendocrine differentiation. Our findings indicate that Trib2 confers resistance to enzalutamide therapy via a mechanism involving increased cellular plasticity and lineage switching.

Lineage Plasticity in Cancer: The Tale of a Skin-Walker

“…Another interesting study has revealed the role of Tribbles 2 (Trib2), a pseudokinase, in mediating antiandrogen resistance in prostate cancer. They found that antiandrogen treatment-resistant cells overexpress Trib2 which can induce lineage switching by upregulation of SOX2 and BRN2 [ 123 ].…”