雄激素受体信号抑制剂（ARSIs）的抵抗性在前列腺癌中是一个重要的临床挑战。我们之前证明了ARSIs药物恩扎鲁胺只能抑制部分与雄激素受体（AR）调控相关的基因，我们假设这些未受影响的基因网络可能成为治疗干预的潜在靶点。本研究确定透明质酸介导的运动受体（HMMR）作为前列腺癌中的一个生存因子，并研究其作为克服抗性ARSI的共同靶点的潜力。我们使用RNA-seq、RT-qPCR和Western Blot来评估AR和ARSIs对HMMR的调控。通过使用siRNA敲除或药物抑制剂4-甲基磷卞吩酮（4-MU），我们在前列腺癌细胞系、小鼠异种移植模型和患者来源的外植体中实现了对HMMR的抑制。HMMR是AR调控的因子，不受ARSIs的影响。通过遗传学（siRNA）或药物（4-MU）抑制HMMR，在荷尔蒙敏感或恩扎鲁胺耐药的前列腺癌模型中明显抑制了细胞增长并诱导了细胞凋亡。机械上讲，4-MU抑制了AR在细胞核的转位、AR蛋白表达以及其下游信号通路。4-MU在体外增强了3种不同的ARSIs对细胞增长的抑制作用，并且与恩扎鲁胺联合使用时，在体内和外植体中能够限制前列腺癌细胞的增殖。共同靶向HMMR和AR是提高对ARSIs应答的有效策略。 ©2023. 作者（们）。

Resistance to androgen receptor signalling inhibitors (ARSIs) represents a major clinical challenge in prostate cancer. We previously demonstrated that the ARSI enzalutamide inhibits only a subset of all AR-regulated genes, and hypothesise that the unaffected gene networks represent potential targets for therapeutic intervention. This study identified the hyaluronan-mediated motility receptor (HMMR) as a survival factor in prostate cancer and investigated its potential as a co-target for overcoming resistance to ARSIs.RNA-seq, RT-qPCR and Western Blot were used to evaluate the regulation of HMMR by AR and ARSIs. HMMR inhibition was achieved via siRNA knockdown or pharmacological inhibition using 4-methylumbelliferone (4-MU) in prostate cancer cell lines, a mouse xenograft model and patient-derived explants (PDEs).HMMR was an AR-regulated factor that was unaffected by ARSIs. Genetic (siRNA) or pharmacological (4-MU) inhibition of HMMR significantly suppressed growth and induced apoptosis in hormone-sensitive and enzalutamide-resistant models of prostate cancer. Mechanistically, 4-MU inhibited AR nuclear translocation, AR protein expression and subsequent downstream AR signalling. 4-MU enhanced the growth-suppressive effects of 3 different ARSIs in vitro and, in combination with enzalutamide, restricted proliferation of prostate cancer cells in vivo and in PDEs.Co-targeting HMMR and AR represents an effective strategy for improving response to ARSIs.© 2023. The Author(s).