APOBEC mutagenesis in EGFR mutant TKI resistance NSCLCs

Receptor tyrosine kinase (RTK)-activated lung cancers are characterized by alterations in oncogenic drivers that induce kinase activation with resultant tyrosine kinase inhibitor (TKI) resistance through both on-target and off-target mechanisms. Focusing on a subgroup of 93 EGFR-mutant lung cancers with paired osimertinib-naïve and osimertinib-resistant tumor samples, we find a significant enrichment of kataegis, chromothripsis and APOBEC mutagenesis among the cancers treated with targeted therapy. APOBEC mutagenesis and structural rearrangements are pervasive mechanisms by which RTK-driven lung cancers may evolve and develop drug resistance.EGA study EGAS00001005526