Adaptive translational reprogramming of metabolism limits the response to targeted therapy in BRAF^V600 melanoma

Area of Science:

• Oncology
• Molecular Biology
• Cancer Metabolism

Background:

• Targeted therapies for oncogene-driven cancers show success but are limited by residual disease and relapse.
• Non-genetic adaptive resistance, particularly altered metabolism, is a key driver of relapse in melanoma.
• Understanding the mechanisms of adaptive resistance is crucial for improving long-term patient outcomes.

Purpose of the Study:

• To investigate how targeted therapy reprograms metabolism in BRAF-mutant melanoma cells.
• To identify key regulators of metabolic adaptation and non-genetic resistance.
• To explore UHMK1 as a potential therapeutic target to overcome resistance to BRAF-targeted therapies.

Main Methods:

• Genome-wide RNA interference (RNAi) screen in BRAF-mutant melanoma cells.
• Global gene expression profiling to analyze metabolic reprogramming.
• Investigation of post-transcriptional regulation, including mRNA transport and translation.
• Validation of UHMK1 function in vitro and in vivo models.

Main Results:

• Targeted therapy induces significant metabolic reprogramming in BRAF-mutant melanoma.
• Post-transcriptional regulation, involving selective mRNA transport and translation, is critical for this adaptation.
• U2AF homology motif kinase 1 (UHMK1) was identified as a key kinase regulating metabolism-associated mRNAs.
• UHMK1 inactivation disrupts metabolic reprogramming, induces cell death, and delays resistance to BRAF/MEK inhibitor therapy in vivo.

Conclusions:

• Selective mRNA processing and translation by UHMK1 is a mechanism of non-genetic resistance in melanoma.
• UHMK1 controls metabolic plasticity induced by targeted therapy.
• Targeting UHMK1 may represent a novel strategy to overcome adaptive resistance and improve efficacy of BRAF-targeted therapies in melanoma.