Work

Precision projections of the delay of resistance mutations in non-small cell lung cancer via suppression of APOBEC

Year: 2025

Type: article

Abstract: Genomic instability driven by stress-response-dependent mutagenesis is a key factor in cancer progression. Tyrosine kinase inhibitor therapy, a common treatment for non-small cell lung cancer, induces mutations that can facilitate the evolution of drug resistance and therapeutic failure. Here we quantified the contribution of APOBEC to mutational signatures in non-small cell lung cancer patients undergoing TKI therapy. By analyzing tumor sequence data to infer gene-specific and patient-specific trinucleotide mutation rates, we projected the potential delay of resistance obtained by suppression of APOBEC mutation. Our data-driven analysis indicates that inhibition of APOBEC activity would substantially extend therapeutic efficacy, with the degree of benefit varying based on patient-specific APOBEC mutagenesis levels. Personalized therapeutic strategies that target APOBEC offer promise for the enhancement of TKI treatment efficacy by delaying the evolution of drug resistance in lung cancer. Development of clinically safe inhibitors for use in combination with tyrosine kinase inhibitors could significantly limit tumor genetic variation and improve outcomes for non-small cell lung cancer patients.

Source: Lung Cancer

DOI: 10.1016/j.lungcan.2025.108487

Authors: Orestis Nousias, Jeffrey D. Mandell, Karen S. Anderson, Jeffrey P. Townsend

Institutions: Yale University, Yale Cancer Center

Language: English

Topic: Lung Cancer Treatments and Mutations

Subfield: Pulmonary and Respiratory Medicine

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: hybrid

Estimated APC paid: $3,390