{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Yu J"],"funding":["Key Program of the Science and Technology Bureau of Sichuan","1.3.5 project for disciplines of excellence, West China Hospital, Sichuan University","the China Postdoctoral Science Foundation under Grant Number","MOST | 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 University","the China Post-doctoral Science Foundation","Sichuan Science and Technology Program"],"pagination":["4180-4196"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC12373858"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["26(16)"],"pubmed_abstract":["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 melano"],"journal":["EMBO reports"],"pubmed_title":["Transcriptome-wide decoding the roles of aberrant splicing in melanoma MAPK-targeted resistance evolution."],"pmcid":["PMC12373858"],"funding_grant_id":["GZC20241148","82304527","82404682","2024M752260","2024NSFSC1765","82102492","2022M722129","ZYGD23028","2022YFA1207300 [2022YFA1207303]","2024NSFSC1725","82172634","2021YFSY0007","2024HXBH138","81902792","2023M742482"],"pubmed_authors":["Jing J","Si L","Ma X","Yu J","Liu X","Li Y","Yu C","He X","Jiang X","Wu S","Luo Y","Wang X","Chen X","Shi H"],"additional_accession":[]},"is_claimable":false,"name":"Transcriptome-wide decoding the roles of aberrant splicing in melanoma MAPK-targeted resistance evolution.","description":"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 melano","dates":{"release":"2025-01-01T00:00:00Z","publication":"2025 Aug","modification":"2026-05-08T06:53:59.518Z","creation":"2026-04-07T23:31:34.949Z"},"accession":"S-EPMC12373858","cross_references":{"pubmed":["40681872"],"doi":["10.1038/s44319-025-00521-6"]}}