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Therapy-induced APOBEC3A drives evolution of persistent cancer cells

Hideko Isozaki1,2, Ramin Sakhtemani3,4, Ammal Abbasi3

  • 1Massachusetts General Hospital Cancer Center, Boston, MA, USA. hisozaki@mgh.harvard.edu.

Nature
|July 5, 2023
PubMed

Insights

Targeted lung cancer therapies can induce APOBEC3A (A3A), causing mutations in persistent cancer cells. Suppressing A3A may delay acquired drug resistance, offering a new therapeutic strategy.

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.

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