雄性激素受体阻断促进对BRAF/MEK靶向疗法的反应-小柯机器人-科学网

雄性激素受体阻断促进对BRAF/MEK靶向疗法的反应

2022-06-19 12:12

美国德克萨斯大学Jennifer A. Wargo等研究人员合作发现，雄性激素受体阻断促进对BRAF/MEK靶向疗法的反应。该项研究成果于2022年6月15日在线发表在《自然》杂志上。

研究人员调查了一组接受新辅助BRAF/MEK靶向治疗的黑色素瘤患者（NCT02231775，n=51），并观察到女性患者与男性患者的主要病理反应（MPR；切除时≤10%的存活肿瘤）率明显较高，无复发生存（RFS）得到改善（MPR，66%对14%，P=0.001；RFS，2年后64%对32%，P=0.021）。这些研究结果在另外几个队列中得到了验证，这些队列中的不可切除的转移性黑色素瘤患者接受了BRAF和/或MEK靶向治疗（共664名患者），在这些研究中，女性患者与男性患者相比，无进展生存期和总生存期都有所改善。

临床前模型的研究表明，BRAF/MEK靶向治疗后雄性小鼠与雌性小鼠的抗肿瘤活性明显受损（P=0.006），雄性和雌性BRAF/MEK治疗的小鼠肿瘤中雄性激素受体的表达明显高于对照组（P=0.0006和P=0.0025）。药物抑制雄性激素受体信号可改善雄性和雌性小鼠对BRAF/MEK靶向治疗的反应（P=0.018和P=0.003），而诱导雄性激素受体信号（通过服用睾丸激素）与雄性和雌性患者对BRAF/MEK靶向治疗的反应明显受损有关（P=0.021和P<0.0001）。总之，这些结果对治疗有重要意义。

据悉，以BRAF和MEK为靶点的治疗已经彻底改变了黑色素瘤和其他癌症的治疗方法；然而，治疗耐药性很普遍，需要创新的治疗策略。

附：英文原文

Title: Androgen receptor blockade promotes response to BRAF/MEK-targeted therapy

Author: Vellano, Christopher P., White, Michael G., Andrews, Miles C., Chelvanambi, Manoj, Witt, Russell G., Daniele, Joseph R., Titus, Mark, McQuade, Jennifer L., Conforti, Fabio, Burton, Elizabeth M., Lastrapes, Matthew J., Ologun, Gabriel, Cogdill, Alexandria P., Morad, Golnaz, Prieto, Peter, Lazar, Alexander J., Chu, Yanshuo, Han, Guangchun, Khan, M. A. Wadud, Helmink, Beth, Davies, Michael A., Amaria, Rodabe N., Kovacs, Jeffrey J., Woodman, Scott E., Patel, Sapna, Hwu, Patrick, Peoples, Michael, Lee, Jeffrey E., Cooper, Zachary A., Zhu, Haifeng, Gao, Guang, Banerjee, Hiya, Lau, Mike, Gershenwald, Jeffrey E., Lucci, Anthony, Keung, Emily Z., Ross, Merrick I., Pala, Laura, Pagan, Eleonora, Segura, Rossana Lazcano, Liu, Qian, Borthwick, Mikayla S., Lau, Eric, Yates, Melinda S., Westin, Shannon N., Wani, Khalida, Tetzlaff, Michael T., Haydu, Lauren E., Mahendra, Mikhila, Ma, XiaoYan, Logothetis, Christopher, Kulstad, Zachary, Johnson, Sarah, Hudgens, Courtney W., Feng, Ningping, Federico, Lorenzo, Long, Georgina V., Futreal, P. Andrew, Arur, Swathi, Tawbi, Hussein A., Moran, Amy E., Wang, Linghua, Heffernan, Timothy P., Marszalek, Joseph R., Wargo, Jennifer A.

Issue&Volume: 2022-06-15

Abstract: Treatment with therapy targeting BRAF and MEK (BRAF/MEK) has revolutionized care in melanoma and other cancers; however, therapeutic resistance is common and innovative treatment strategies are needed1,2. Here we studied a group of patients with melanoma who were treated with neoadjuvant BRAF/MEK-targeted therapy (NCT02231775, n=51) and observed significantly higher rates of major pathological response (MPR; ≤10% viable tumour at resection) and improved recurrence-free survival (RFS) in female versus male patients (MPR, 66% versus 14%, P=0.001; RFS, 64% versus 32% at 2 years, P=0.021). The findings were validated in several additional cohorts2,3,4 of patients with unresectable metastatic melanoma who were treated with BRAF- and/or MEK-targeted therapy (n=664 patients in total), demonstrating improved progression-free survival and overall survival in female versus male patients in several of these studies. Studies in preclinical models demonstrated significantly impaired anti-tumour activity in male versus female mice after BRAF/MEK-targeted therapy (P=0.006), with significantly higher expression of the androgen receptor in tumours of male and female BRAF/MEK-treated mice versus the control (P=0.0006 and P=0.0025). Pharmacological inhibition of androgen receptor signalling improved responses to BRAF/MEK-targeted therapy in male and female mice (P=0.018 and P=0.003), whereas induction of androgen receptor signalling (through testosterone administration) was associated with a significantly impaired response to BRAF/MEK-targeted therapy in male and female patients (P=0.021 and P<0.0001). Together, these results have important implications for therapy.

DOI: 10.1038/s41586-022-04833-8

Source: https://www.nature.com/articles/s41586-022-04833-8

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html

本期文章：《自然》：Online/在线发表

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