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<p>Drug resistance critically limits the long-term efficacy of MAPK-targeted therapy in melanoma. While resistance mechanisms at genetic, epigenetic, and transcriptional scales are well-documented, post-transcriptional splicing regulation remains poorly understood. By analyzing patient-matched pre-treatment and resistant melanoma biopsies, we uncover widespread alternative splicing alterations during therapy resistance. Splicing perturbations are most pronounced in MAPK and PI3K-AKT pathway genes. We identify a splicing switch of AKT2 from isoform 210 to 206 in 29.55% (13/44) of disease-progressive biopsies. This splicing switch induces AKT2 kinase hyperactivity by restoring the activated fragment A-loop. Functional validations confirm that AKT2-206 confers BRAF inhibitor resistance in melanoma cells by activating S6 kinase. Further, the splicing factor hnRNPK likely drives the splicing switch of AKT2 during acquired resistance. Our results not only provide insights into splicing-mediated regulation of drug resistance but also highlight the importance of alternative splicing isoforms as targets for clinical diagnosis and therapy.</p>

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Transcriptome-wide decoding the roles of aberrant splicing in melanoma MAPK-targeted resistance evolution

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月18日

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  • Jing Yu,
  • Xiujing He,
  • Xueyan Wang,
  • Chune Yu,
  • Xian Jiang,
  • Yanna Li,
  • Xinyu Liu,
  • Ya Luo,
  • Xuemei Chen,
  • Sisi Wu,
  • Lu Si,
  • Jing Jing,
  • Xuelei Ma,
  • Hubing Shi

摘要

Drug resistance critically limits the long-term efficacy of MAPK-targeted therapy in melanoma. While resistance mechanisms at genetic, epigenetic, and transcriptional scales are well-documented, post-transcriptional splicing regulation remains poorly understood. By analyzing patient-matched pre-treatment and resistant melanoma biopsies, we uncover widespread alternative splicing alterations during therapy resistance. Splicing perturbations are most pronounced in MAPK and PI3K-AKT pathway genes. We identify a splicing switch of AKT2 from isoform 210 to 206 in 29.55% (13/44) of disease-progressive biopsies. This splicing switch induces AKT2 kinase hyperactivity by restoring the activated fragment A-loop. Functional validations confirm that AKT2-206 confers BRAF inhibitor resistance in melanoma cells by activating S6 kinase. Further, the splicing factor hnRNPK likely drives the splicing switch of AKT2 during acquired resistance. Our results not only provide insights into splicing-mediated regulation of drug resistance but also highlight the importance of alternative splicing isoforms as targets for clinical diagnosis and therapy.