Adaptive mutability of colorectal cancers in response to targeted therapies

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Drug resistance is a major challenge in cancer therapy, often attributed to pre-existing resistant cells.
• Adaptive mutability, where organisms increase mutation rates under stress, is known in bacteria but less understood in human cancers.

Purpose of the Study:

• To investigate if human colorectal cancer (CRC) cells utilize adaptive mutability to evade targeted therapy.
• To understand the molecular mechanisms underlying therapy-induced mutability in CRC.

Main Methods:

• Inhibition of epidermal growth factor receptor (EGFR)/BRAF pathways in CRC cells.
• Analysis of DNA repair gene expression (mismatch repair and homologous recombination).
• Assessment of DNA damage, mutation rates, and microsatellite instability in drug-tolerant cells and patient-derived xenografts.

Main Results:

• EGFR/BRAF inhibition led to down-regulation of DNA repair genes and up-regulation of error-prone polymerases in persister cells.
• MMR protein levels decreased in patient-derived xenografts and tumor specimens during therapy.
• Targeted therapy induced DNA damage, increased cellular mutability, and triggered microsatellite instability.

Conclusions:

• Human colorectal cancer cells can enhance their mutability to evade therapeutic pressure, similar to unicellular organisms.
• Adaptive mutability represents a novel mechanism of drug resistance in cancer that warrants further investigation.