BRAF- and MEK-Targeted Small Molecule Inhibitors Exert Enhanced Antimelanoma Effects in Combination With Oncolytic...

Area of Science:

• Oncology
• Virology
• Molecular Biology

Background:

• Reovirus type 3 (Dearing) (RT3D) selectively infects cells with activated RAS pathways.
• Melanoma harbors RAS and BRAF mutations, influencing signaling pathways like ERK1/2.
• Targeting these pathways with inhibitors offers potential therapeutic strategies.

Purpose of the Study:

• To evaluate therapeutic combinations of RT3D with BRAF/MEK inhibitors in melanoma cell lines.
• To assess the impact of these combinations on ERK1/2 signaling and cell viability.
• To investigate the underlying mechanisms of enhanced cell death and efficacy in preclinical models.

Main Methods:

• Utilized a panel of melanoma cell lines with varying RAS/BRAF mutation statuses.
• Administered RT3D in combination with BRAF inhibitor PLX4720 and MEK inhibitor PD184352.
• Assessed cytotoxicity, ERK1/2 signaling, viral replication (TCID50 assays), and ER stress-induced apoptosis.
• Evaluated in vivo efficacy in both immune-deficient and immune-competent melanoma models.

Main Results:

• RT3D plus BRAF inhibition enhanced cell kill in BRAF-mutated melanoma cells, not RAS-mutated cells.
• RT3D plus MEK inhibition resulted in enhanced cell kill across all tested melanoma cell lines.
• Inhibitors did not affect viral replication; enhanced efficacy stemmed from ER stress-induced apoptosis.
• Combined treatments demonstrated significant in vivo activity against BRAF-mutant melanoma tumors.

Conclusions:

• Combination of RT3D with BRAF inhibitors is effective in BRAF-mutant melanoma.
• Combination of RT3D with MEK inhibitors shows efficacy in both BRAF and RAS mutant melanoma.
• These findings support clinical translation of RT3D combined with BRAF/MEK inhibitors for melanoma treatment.