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

## TL;DR

This study finds that androgen receptor signaling helps melanoma cells resist BRAF inhibitors by boosting autophagy, suggesting new treatment combinations.

## Contribution

The paper identifies AR-driven autophagy as a novel resistance mechanism and proposes a preclinical strategy combining AR degraders and autophagy inhibitors.

## Key findings

- BRAFi treatment increases AR expression, which activates DRAM1 to induce cytoprotective autophagy.
- AR-driven autophagy enhances cell survival under BRAFi stress, leading to resistance.
- Combining AR-targeting PROTAC ARV110 with autophagy inhibitors may overcome BRAFi resistance.

## Abstract

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.