Therapy-Induced APOBEC3A Drives Evolution of Resistance to Targeted Therapies in Non-Small Cell Lung Cancer

The purpose of this study was to identify mechanisms of resistance and associated mutational signatures in non-small cell lung cancers (NSCLCs) treated with targeted therapies. Whole genome sequencing (WGS) and whole exome sequencing (WES) were performed on tumor tissue or cell lines derived from oncogene-driven NSCLCs before and after treatments with tyrosine kinase inhibitors. Somatic mutations were called and mutational signature analysis was performed, revealing enrichment of APOBEC mutational signatures mutational signatures in post-treatment tumors after the development to resistance to targeted therapies. The cohort includes WGS and WES data of tumor and normal tissues from patients with oncogene-driven NSCLCs harboring EGFR mutations, ALK fusions or NTRK1 fusions, who were treated with molecularly targeted therapies that target these oncogenes.]]> Inclusion Criteria1. Diagnosis of advanced non-small cell lung cancer2. Presence of oncogenic driver alteration in EGFR, ALK or NTRK1 genes3. Treatment with one or more genotype-directed therapies (EGFR inhibitor, ALK inhibitor, TRK inhibitor)Exclusion Criteria1. Age less than 18 years]]>