Targeting RPS6KC1 to overcome enzalutamide resistance in prostate cancer

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Enzalutamide (Enz) is a primary therapy for advanced prostate cancer (PCa).
• Most patients develop resistance to Enz, necessitating new therapeutic strategies.
• Understanding the mechanisms of Enzalutamide resistance is crucial for improving PCa treatment outcomes.

Purpose of the Study:

• To identify novel genes and pathways involved in enzalutamide resistance in prostate cancer.
• To elucidate the molecular mechanisms by which resistance develops.
• To explore potential therapeutic strategies to overcome enzalutamide resistance.

Main Methods:

• Integrated analysis of CRISPR genome-wide and kinome-wide screens.
• Expression analysis in enzalutamide-resistant cell lines and PCa tumor tissues.
• Investigation of the H3K18 lactylation, NF-κB, RPS6KC1, and PRDX3 axis.

Main Results:

• RPS6KC1 was identified as a novel essential gene conferring enzalutamide resistance.
• The Warburg effect-induced H3K18 lactylation regulates RPS6KC1 expression via P65 (NF-κB).
• RPS6KC1 recruits PRDX3 to mitochondria, inhibiting ferroptosis and promoting resistance.

Conclusions:

• The H3K18la/NF-κB/RPS6KC1/PRDX3 axis is critical for enzalutamide resistance in PCa.
• Targeting RPS6KC1 or inducing ferroptosis alongside enzalutamide may overcome resistance.
• This study offers a promising therapeutic strategy for advanced prostate cancer patients resistant to enzalutamide.