Targeting ER stress-induced autophagy overcomes BRAF inhibitor resistance in melanoma

Area of Science:

• Oncology
• Molecular Biology
• Cellular Biology

Background:

• BRAF mutations drive melanoma growth and are targeted by BRAF inhibitors (BRAFi).
• Acquired resistance to BRAFi is a major clinical challenge in melanoma treatment.
• The role of therapy-induced autophagy in BRAFi resistance is not fully understood.

Purpose of the Study:

• To investigate the role of autophagy as an adaptive resistance mechanism to BRAFi in melanoma.
• To identify the molecular pathways linking BRAFi, endoplasmic reticulum (ER) stress, and autophagy.
• To evaluate the therapeutic potential of combining BRAFi with autophagy inhibitors.

Main Methods:

• Analysis of tumor biopsies from melanoma patients treated with BRAFi or BRAFi plus MEK inhibitors.
• In vitro studies using BRAF(V600E) melanoma cell lines treated with BRAFi, BRAF/MEK inhibitors, and autophagy inhibitors.
• Investigation of the interaction between BRAF, GRP78, and PERK signaling in response to BRAFi.
• Evaluation of combination therapy in BRAFi-resistant xenograft models.

Main Results:

• BRAFi-resistant melanomas exhibited increased autophagy levels.
• Higher autophagy levels correlated with lower response rates and shorter progression-free survival in patients.
• BRAFi and BRAF/MEK inhibition induced cytoprotective autophagy in melanoma cell lines.
• Autophagy inhibition sensitized melanoma cells to BRAFi-induced death.
• BRAFi treatment led to ER expansion and a PERK-dependent ER stress response activating autophagy.
• Combined BRAFi and autophagy inhibition resulted in tumor regression in resistant xenografts.

Conclusions:

• Therapy-induced autophagy is a key mechanism of adaptive resistance to BRAFi in melanoma.
• A pathway involving BRAFi, ER stress, and autophagy drives drug resistance.
• Combining BRAFi with autophagy inhibitors offers a promising strategy to overcome BRAFi resistance and improve treatment outcomes.