Transient Splicing-Associated Isoform Remodeling Defines Early MAPKi Resistance Adaptation in Melanoma

MAPKi adaptation in BRAF-mutant melanoma is marked by transient, splicing-associated transcript isoform remodeling that peaks during on-treatment/minimal residual disease and attenuates once resistance is established.

• Why it matters: Tumors can rapidly enter drug-tolerant states before stable resistance forms, but the molecular switch enabling this transition is poorly understood when conventional gene-expression analysis misses key changes.
• What they did: The study integrated bulk and single-cell RNA-seq from melanoma cell lines, murine models, patient-derived xenografts, and patient tumors, using differential transcript usage and independent exon-usage analyses across no-treatment, on-treatment/minimal residual disease, and acquired-resistant states.
• The result: Differential transcript usage peaks during the adaptive on-treatment phase, often without total gene-expression changes, and isoform-level features better identify the adaptive state than gene-expression models in independent PDX and patient datasets.