Integrative multi-omics defines melanoma drug response networks and ARID1A-dependent resistance mechanisms

Journal article

Resistance to BRAF/MAPK inhibitors is a significant challenge in melanoma treatment, driven by adaptive and acquired mechanisms allowing tumor cells to evade therapy. We explored early signaling responses to BRAF and MAPK inhibition in a BRAFV600E-sensitive melanoma cell line and a drug-resistant ARID1A-knockout (KO) derivative. ARID1A, frequently mutated in melanoma, is linked to resistance and immune evasion. Through an innovative systems biology approach integrating multi-omics datasets, we identified critical resistance mechanisms. We found that ARID1A-KO cells exhibited transcriptional rewiring, sustaining MAPK1/3 and JNK activity post-treatment, suppressing PRKD1 activation, increasing JUN activity, and disrupting PKC dynamics via elevated RTKs (e.g., EGFR, ROS1) and Ephrin receptor activity. ARID1A-KO also reduced HLA-related protein expression and enhanced extracellular matrix components, potentially limiting immune infiltration and immunotherapy efficacy. Our multi-omics analysis revealed PRKD1, JUN, and NCK1 as key resistance nodes, offering potential targets for therapeutic strategies to counter resistance in melanoma.

Authors: Barker, CG; Sharma, S; Santos, AM; Nikolakopoulos, K; Velentzas, AD

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Springer
• Journal: Molecular Systems Biology
• Volume: 22
• Issue: 5
• Pages: 685-711
• Publication date: 2026-02-18
• Acceptance date: 2025-12-10
• DOI: 10.1038/s44320-025-00183-5
• EISSN: 1744-4292
• ISSN: 1744-4292
• Language: English
• Keywords: Network Analysis; Melanoma; ARID1A; Drug Resistance; Data Integration