Allosteric inhibition of HSP70 in collaboration with STUB1 augments enzalutamide efficacy in antiandrogen resistant prostate tumor and patient-derived models

by Selleckchem | May 13 2023

Ubiquitin proteasome activity is suppressed in enzalutamide resistant prostate cancer cells, and the heat shock protein 70/STIP1 homology and U-box-containing protein 1 (HSP70/STUB1) machinery are involved in androgen receptor (AR) and AR variant protein stabilization. Targeting HSP70 could be a viable strategy to overcome resistance to androgen receptor signaling inhibitor (ARSI) in advanced prostate cancer. Here, we showed that a novel HSP70 allosteric inhibitor, JG98, significantly suppressed drug-resistant C4-2B MDVR and CWR22Rv1 cell growth, and enhanced enzalutamide treatment. JG98 also suppressed cell growth in conditional reprogramed cell cultures (CRCs) and organoids derived from advanced prostate cancer patient samples. Mechanistically, JG98 degraded AR/AR-V7 expression in resistant cells and promoted STUB1 nuclear translocation to bind AR-V7. Knockdown of the E3 ligase STUB1 significantly diminished the anticancer effects and partially restored AR-V7 inhibitory effects of JG98. JG231, a more potent analog developed from JG98, effectively suppressed the growth of the drug-resistant prostate cancer cells, CRCs, and organoids. Notably, the combination of JG231 and enzalutamide synergistically inhibited AR/AR-V7 expression and suppressed CWR22Rv1 xenograft tumor growth. Inhibition of HSP70 using novel small-molecule inhibitors coordinates with STUB1 to regulate AR/AR-V7 protein stabilization and ARSI resistance.

Comments：

The passage describes a study that investigated the use of HSP70 allosteric inhibitors to overcome resistance to androgen receptor signaling inhibitors (ARSI) in advanced prostate cancer. The researchers found that a novel HSP70 inhibitor called JG98 significantly suppressed the growth of drug-resistant prostate cancer cells and enhanced the effects of enzalutamide, an ARSI drug. JG98 also suppressed cell growth in patient-derived samples of advanced prostate cancer.

The mechanism of action of JG98 involved degrading the expression of AR/AR-V7, which are proteins involved in ARSI resistance. JG98 also promoted the nuclear translocation of the E3 ligase STUB1, which bound to AR-V7, further inhibiting its activity. Knockdown of STUB1 partially restored the inhibitory effects of JG98 on AR-V7, suggesting that the two work together to regulate AR/AR-V7 protein stabilization and ARSI resistance.

The researchers also developed a more potent analog of JG98 called JG231, which effectively suppressed the growth of drug-resistant prostate cancer cells, CRCs, and organoids. In combination with enzalutamide, JG231 synergistically inhibited AR/AR-V7 expression and suppressed CWR22Rv1 xenograft tumor growth.

Overall, these findings suggest that targeting HSP70 using novel small-molecule inhibitors, in combination with ARSI drugs, could be a viable strategy to overcome resistance to ARSI in advanced prostate cancer.