biostudies-literatureYu JKey Program of the Science and Technology Bureau of Sichuan1.3.5 project for disciplines of excellence, West China Hospital, Sichuan Universitythe China Postdoctoral Science Foundation under Grant NumberMOST | National Key Research and Development Program of China (NKPs)MOST | National Natural Science Foundation of China (NSFC)Post-doctoral Research Project, West China Hospital, Sichuan Universitythe China Post-doctoral Science FoundationSichuan Science and Technology Program4180-4196https://www.ebi.ac.uk/biostudies/studies/S-EPMC12373858biostudies-literatureUnknown26(16)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 melanoEMBO reportsTranscriptome-wide decoding the roles of aberrant splicing in melanoma MAPK-targeted resistance evolution.PMC12373858GZC2024114882304527824046822024M7522602024NSFSC1765821024922022M722129ZYGD230282022YFA1207300 [2022YFA1207303]2024NSFSC1725821726342021YFSY00072024HXBH138819027922023M742482Jing JSi LMa XYu JLiu XLi YYu CHe XJiang XWu SLuo YWang XChen XShi HfalseTranscriptome-wide decoding the roles of aberrant splicing in melanoma MAPK-targeted resistance evolution.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 melano2025-01-01T00:00:00Z2025 Aug2026-05-08T06:53:59.518Z2026-04-07T23:31:34.949ZS-EPMC123738584068187210.1038/s44319-025-00521-6