Selective mRNA translation determines adaptative mutability of melanoma cells to anti-BRAF/MEK combination therapy

Area of Science:

• Cancer Biology
• Molecular Oncology
• Drug Resistance Mechanisms

Background:

• Cancer cells adapt to targeted therapies through altered gene expression, increasing mutation rates and acquiring resistance.
• Drug tolerance in melanoma involves adaptive mechanisms that promote the evolution of resistance to therapies like BRAF and MEK inhibitors.

Purpose of the Study:

• To investigate the role of translational control in mediating adaptive mutability in drug-tolerant melanoma cells.
• To identify key regulators of translational control involved in the evolution of melanoma drug resistance.
• To evaluate the therapeutic potential of targeting translational machinery to overcome acquired resistance.

Main Methods:

• Analysis of gene expression profiles in drug-tolerant melanoma cells.
• Investigating the regulation of non-homologous end joining (NHEJ) component 53BP1 translation.
• Utilizing small molecule inhibitors of the eIF4A RNA helicase in melanoma cell lines and xenograft models.

Main Results:

• Translational control of 53BP1 mRNA is crucial for NHEJ and mutability in drug-tolerant melanoma cells.
• The eIF4A RNA helicase regulates 53BP1 mRNA translation.
• Targeting eIF4A with inhibitors significantly delays resistance acquisition in BRAF-mutant melanoma models by reducing cell mutability.

Conclusions:

• Translational control, specifically of 53BP1, is a key mediator of adaptive mutability in melanoma drug tolerance.
• Targeting the eIF4A RNA helicase represents a promising strategy to overcome acquired resistance to BRAF and MEK inhibitors in melanoma.
• Standard-of-care therapies can inadvertently drive the evolution of drug tolerance and resistance through translational adaptation.