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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月18日

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  • Charlie George Barker,
  • Sumana Sharma,
  • Ana Mafalda Santos,
  • Konstantinos-Stylianos Nikolakopoulos,
  • Athanassios D Velentzas,
  • Cristina Tormo-Garcia,
  • Anushka Sharma,
  • Franziska I Völlmy,
  • Angeliki Minia,
  • Vicky Pliaka,
  • Joseph Clarke,
  • Maarten Altelaar,
  • Gavin J Wright,
  • Leonidas G Alexopoulos,
  • Dimitrios J Stravopodis,
  • Evangelia Petsalaki

摘要

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.