Therapy-induced APOBEC3A drives evolution of persistent cancer cells

Area of Science:

• Oncology
• Genetics
• Molecular Biology

Background:

• Acquired drug resistance to targeted anticancer therapies is a major clinical challenge.
• Mechanisms of tumor evolution during therapy, particularly regarding drug resistance, are not fully understood.
• Genomic studies suggest a role for Apolipoprotein B messenger RNA editing catalytic polypeptide-like (APOBEC) cytidine deaminases in tumor evolution.

Purpose of the Study:

• To investigate the role of APOBEC cytidine deaminases, specifically APOBEC3A (A3A), in the development of acquired drug resistance during lung cancer targeted therapy.
• To determine if targeted therapies induce A3A and if this contributes to tumor evolution and resistance.

Main Methods:

• Analysis of lung cancer cells and patient tumors.
• Assessment of A3A induction by targeted therapies.
• Evaluation of APOBEC-mediated mutagenesis and genomic instability in drug-tolerant persister cells.
• Genetic deletion of A3A to assess its impact on resistance.
• Analysis of APOBEC mutational signatures in patient tumors.

Main Results:

• Common lung cancer targeted therapies induce APOBEC3A (A3A) in drug-tolerant persister cells.
• Therapy-induced A3A leads to sustained mutagenesis and increased genomic instability.
• Deletion of A3A reduced APOBEC mutations and structural variations, delaying drug resistance.
• APOBEC mutational signatures were found in lung cancer patients who developed resistance after initial response.

Conclusions:

• Induction of A3A by targeted therapies drives the evolution of drug-tolerant persister cells.
• A3A plays a significant role in acquired drug resistance in lung cancer.
• Suppression of A3A activity or expression could be a therapeutic strategy to prevent or delay resistance to lung cancer targeted therapies.