Modulating autophagy in KRAS mutant colorectal cancer using combination of oncolytic reovirus and carbamazepine

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Oncolytic reovirus demonstrates potential for treating colorectal cancer (CRC) with KRAS mutations by inducing apoptosis via autophagy.
• Current limitations of reovirus monotherapy necessitate combination strategies for enhanced efficacy.
• Carbamazepine, an anticonvulsant, is known to induce autophagy and is investigated as a potentiator for reovirus therapy.

Purpose of the Study:

• To evaluate the synergistic effect of combining oncolytic reovirus with carbamazepine in KRAS-mutant colorectal cancer models.
• To investigate the impact of this combination therapy on cancer cell viability and the underlying autophagic mechanisms.

Main Methods:

• Treatment of KRAS-mutant and wildtype CRC cell lines with reovirus and/or carbamazepine.
• Assessment of cell viability using standard assays.
• Analysis of autophagy-related protein and mRNA expression.
• Transmission electron microscopy to visualize autophagosome formation and chromatin condensation.

Main Results:

• The combination of carbamazepine and reovirus significantly reduced cancer cell viability in KRAS-mutant CRC lines compared to reovirus alone.
• Dual treatment led to increased expression of autophagy-related proteins and mRNA in KRAS-mutant cells.
• Transmission electron microscopy confirmed enhanced autophagosome formation and reduced condensed chromatin in combination-treated cells.

Conclusions:

• Combination therapy with oncolytic reovirus and carbamazepine is a viable and effective strategy for enhancing apoptosis in KRAS-mutant colorectal cancer.
• This approach potentiates reovirus-induced cell death by modulating autophagic pathways, offering a promising therapeutic option for this patient subgroup.