Brain microenvironment-driven resistance to immune and targeted therapies in acral melanoma

Area of Science:

• Oncology
• Melanoma Research
• Cancer Immunology

Background:

• Combination treatments targeting the MEK-ERK pathway and checkpoint inhibitors have improved melanoma survival.
• Resistance to these therapies, particularly in the brain, remains a significant clinical challenge.
• Rare subtypes like acral melanoma are often underrepresented in clinical trials.

Purpose of the Study:

• To investigate resistance mechanisms in a patient with metastatic acral melanoma progressing on immune and targeted therapies.
• To analyze longitudinal tumor samples and patient-derived models to understand treatment failure.

Main Methods:

• Whole-exome sequencing and RNA sequencing of acral melanoma samples.
• In vitro growth inhibition assays and proteomic analysis (reverse phase protein arrays) of patient-derived cell lines.
• Development and analysis of patient-derived xenografts to assess response to targeted therapy.

Main Results:

• Immune escape was linked to microenvironmental changes, not loss of tumor recognition or low neoantigen burden.
• Resistance to targeted therapy (dabrafenib) was associated with AKT/phospho-inositide 3-kinase pathway upregulation in the presence of cerebrospinal fluid (CSF), not acquired mutations.
• Cerebrospinal fluid influenced targeted therapy resistance.

Conclusions:

• Heterogeneous tumor interactions within the brain microenvironment contribute to treatment progression.
• These microenvironmental factors are critical targets for developing salvage therapies in resistant melanoma.