Targeting the metabolic enzyme PGAM2 overcomes enzalutamide resistance in castration-resistant prostate cancer by inhibiting BCL2 signaling.

The next-generation androgen receptor (AR) inhibitor enzalutamide (ENZ) is the mainstay treatment for metastatic prostate cancer. Unfortunately, resistance occurs rapidly in most patients, and once resistance occurs treatment options are limited. Therefore, there is an urgent need to identify effective targets to overcome ENZ resistance. Here, using a genome-wide CRISPR-Cas9 library screen, we found that targeting a glycolytic enzyme, phosphoglycerate mutase PGAM2, significantly enhanced the sensitivity of ENZ-resistant prostate cancer cells to ENZ both in vivo and in vitro. Inhibition of PGAM2 together with ENZ treatment triggered apoptosis by decreasing levels of the anti-apoptotic protein BCL-xL and increasing activity of the pro-apoptotic protein BAD. Mechanistically, PGAM2 bound to 14-3-3ζ and promoted its interaction with phosphorylated BAD, resulting in activation of BCL-xL and subsequent resistance to ENZ-induced apoptosis. In addition, high PGAM2 expression, which is transcriptionally regulated by AR, was associated with shorter survival and rapid development of ENZ resistance in prostate cancer patients. Together, these findings provide evidence of a non-metabolic function of PGAM2 in promoting ENZ resistance and identify PGAM2 inhibition as a promising therapeutic strategy for ENZ-resistant prostate cancer.