Overexpression of ATP-binding cassette subfamily B member 1 (ABCB1)–encoded multidrug resistance protein 1 (MDR1) constitutes a major mechanism of cancer drug resistance including docetaxel (DTX) and cabazitaxel (CTX) resistance in castration-resistant prostate cancer (CRPC). However, no therapeutics that targets MDR1 is available at clinic for taxane sensitization. We report here that retinoic acid receptor-related orphan receptor γ (RORγ), a nuclear receptor family member, unexpectedly mediates MDR1/ABCB1 overexpression. RORγ plays an important role in controlling the functions of subsets of immune cells and has been an attractive target for autoimmune diseases. We found that its small-molecule antagonists are efficacious in resensitizing DTX and CTX cross-resistant CRPC cells and tumors to taxanes in both androgen receptor–positive and –negative models. Our mechanistic analyses revealed that combined treatment with RORγ antagonists and taxane elicited a robust synergy in killing the resistant cells, which involves a coordinated alteration of p53, Myc, and E2F-controlled programs critical for both intrinsic and extrinsic apoptosis, survival, and cell growth. Our results suggest that targeting RORγ with small-molecule inhibitors is a novel strategy for chemotherapy resensitization in tumors with MDR1 overexpression.

中文翻译：

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RORγ拮抗剂靶向MDR1表达的治疗通过协同诱导细胞死亡程序使交叉耐药的CRPC对紫杉烷重新敏感

ATP 结合盒亚家族 B 成员 1 (ABCB1) 编码的多药耐药蛋白 1 (MDR1) 的过度表达构成了癌症耐药性的主要机制，包括去势抵抗性前列腺癌 (CRPC) 中多西他赛 (DTX) 和卡巴他赛 (CTX) 耐药性. 然而，临床上没有针对 MDR1 的疗法可用于紫杉烷致敏。我们在此报告视黄酸受体相关孤儿受体 γ (RORγ)，一种核受体家族成员，出人意料地介导 MDR1/ABCB1 过表达。RORγ 在控制免疫细胞亚群的功能方面发挥着重要作用，并且一直是自身免疫性疾病的一个有吸引力的目标。我们发现，在雄激素受体阳性和阴性模型中，其小分子拮抗剂可有效使 DTX 和 CTX 交叉耐药的 CRPC 细胞和肿瘤对紫杉烷类药物重新敏感。我们的机制分析表明，RORγ 拮抗剂和紫杉烷的联合治疗在杀死耐药细胞方面引发了强大的协同作用，这涉及 p53、Myc 和 E2F 控制程序的协调改变，这些程序对内在和外在的细胞凋亡、存活和细胞生长都至关重要. 我们的研究结果表明，用小分子抑制剂靶向 RORγ 是 MDR1 过表达肿瘤化疗再敏化的新策略。这涉及 p53、Myc 和 E2F 控制程序的协调改变，这些程序对内在和外在的细胞凋亡、存活和细胞生长都至关重要。我们的研究结果表明，用小分子抑制剂靶向 RORγ 是 MDR1 过表达肿瘤化疗再敏化的新策略。这涉及 p53、Myc 和 E2F 控制程序的协调改变，这些程序对内在和外在的细胞凋亡、存活和细胞生长都至关重要。我们的研究结果表明，用小分子抑制剂靶向 RORγ 是 MDR1 过表达肿瘤化疗再敏化的新策略。