Scholarlink

<p>BRAFV600-mutant melanoma relies on hyperactivation of the MAPK/ERK pathway for tumorigenesis, with BRAF/MEK inhibitors (BRAFi/MEKi) improving patient outcomes. However, therapeutic resistance frequently emerges, and male patients show poorer responses and outcomes, partially linked to androgen receptor (AR) overexpression. Here, we uncover a mechanistic link between AR signaling and autophagic resistance in BRAFV600-mutant melanoma. We show that BRAFi treatment upregulates AR expression, which induces cytoprotective autophagy through transcriptional activation of DRAM1, a key autophagy-related gene. Functional studies reveal that AR-driven autophagy confers resistance to BRAFi by enhancing cellular survival under therapeutic stress. Our findings establish AR-regulated autophagy as a critical resistance mechanism and provide preclinical evidence for combining AR-targeting PROTAC degrader ARV110 with autophagy inhibitors to overcome BRAFi resistance.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Androgen receptor-dependent DRAM1 activation drives autophagic resistance to BRAF inhibitors in BRAFV600-mutant melanoma

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年3月16日

查看全文
  • Ding Zhi,
  • Baojin Wu,
  • Junyi Yang,
  • Daohe Wang,
  • Jing Qiao,
  • Fanli Guo

摘要

BRAFV600-mutant melanoma relies on hyperactivation of the MAPK/ERK pathway for tumorigenesis, with BRAF/MEK inhibitors (BRAFi/MEKi) improving patient outcomes. However, therapeutic resistance frequently emerges, and male patients show poorer responses and outcomes, partially linked to androgen receptor (AR) overexpression. Here, we uncover a mechanistic link between AR signaling and autophagic resistance in BRAFV600-mutant melanoma. We show that BRAFi treatment upregulates AR expression, which induces cytoprotective autophagy through transcriptional activation of DRAM1, a key autophagy-related gene. Functional studies reveal that AR-driven autophagy confers resistance to BRAFi by enhancing cellular survival under therapeutic stress. Our findings establish AR-regulated autophagy as a critical resistance mechanism and provide preclinical evidence for combining AR-targeting PROTAC degrader ARV110 with autophagy inhibitors to overcome BRAFi resistance.