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

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Drug resistance limits MAPK-targeted therapy efficacy in melanoma.
• Mechanisms of resistance are known at genetic, epigenetic, and transcriptional levels.
• Post-transcriptional splicing regulation in melanoma drug resistance is poorly understood.

Purpose of the Study:

• To investigate alternative splicing alterations in melanoma during acquired therapy resistance.
• To identify specific splicing events and their functional consequences in BRAF inhibitor resistance.
• To explore the role of splicing factors in mediating resistance mechanisms.

Main Methods:

• Analysis of patient-matched pre-treatment and resistant melanoma biopsies.
• Identification and validation of alternative splicing events using molecular techniques.
• Functional studies in melanoma cell lines to assess the impact of splicing alterations on drug resistance.

Main Results:

• Widespread alternative splicing alterations were observed during melanoma therapy resistance.
• Splicing perturbations were most prominent in MAPK and PI3K-AKT pathway genes.
• A switch from AKT2 isoform 210 to 206 was identified in resistant biopsies, leading to kinase hyperactivity and BRAF inhibitor resistance via S6 kinase activation.
• The splicing factor hnRNPK was implicated in driving the AKT2 splicing switch.

Conclusions:

• Alternative splicing plays a significant role in melanoma drug resistance.
• The AKT2 splicing switch is a key mechanism conferring resistance to BRAF inhibitors.
• Alternative splicing isoforms represent potential targets for clinical diagnosis and therapy in melanoma.