Repurposing Metabolic Inhibitors in the Treatment of Colon Adenocarcinoma Patient-Derived Models

Area of Science:

• Oncology
• Molecular Biology
• Metabolic Pathways

Background:

• AMP-activated protein kinase (AMPK) agonists like metformin and phenformin show promise in cancer treatment.
• Phenformin exhibits antitumor activity, particularly in melanomas with BRAF mutations.

Purpose of the Study:

• To investigate the synergistic antitumor effects of biguanides combined with metabolic inhibitors in colon tumors.
• To evaluate the efficacy of phenformin and 2-deoxy-D-glucose (2DG) in preclinical colon cancer models.

Main Methods:

• Utilized cancer cell lines (including HT29 with BRAF/p53 mutations) and patient-derived models (xenografts and organoids).
• Assessed tumor growth inhibition, cell cycle arrest, apoptosis, and autophagy.
• Analyzed effects on phosphorylated ERK and mutant p53 protein.

Main Results:

• Phenformin combined with 2DG inhibited colon tumor cell growth, inducing cell cycle arrest, apoptosis, and autophagy.
• The combination therapy demonstrated activity against phosphorylated ERK and mutant p53.
• Co-treatment significantly reduced the growth of patient-derived colon models compared to single-agent treatment.

Conclusions:

• Biguanides, such as phenformin, synergize with metabolic inhibitors like 2DG to inhibit colon tumor growth.
• Combination therapy targeting AMPK activation and cancer metabolism offers significant therapeutic advantages.
• This approach holds promise for treating colon cancers, including those with specific mutations.