The following is the summary of “APOBEC mutagenesis, kataegis, chromothripsis in EGFR-mutant osimertinib-resistant lung adenocarcinomas” published in the December 2022 issue of Oncology by Selenica, et al.
To date, most research on resistance to targeted therapy in lung cancer has concentrated on the role of single-gene changes. Researchers hypothesized that mutational signature analysis might aid in elucidating acquired resistance to targeted therapies based on previous work linking apolipoprotein b mRNA-editing enzyme, catalytic polypeptide-like (APOBEC) mutagenesis to the histological transformation of epidermal growth factor receptor (EGFR)-mutant lung cancers. Signature Multivariate Analysis (SigMA) was used to compare APOBEC mutational signatures generated from an FDA-cleared multigene panel Memorial Sloan Kettering Cancer Center Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) to the gold standard of mutational signatures generated from whole-exome sequencing. Mutational signatures were deconstructed in 3,276 distinct lung adenocarcinomas (LUADs), including 93 paired osimertinib-naïve and -resistant EGFR-mutant tumors.
Investigators looked into whether or not APOBEC was connected to osimertinib resistance mechanisms. In order to examine large-scale genomic abnormalities that may contribute to osimertinib resistance, we sequenced the whole genomes of the 30 available EGFR-mutant lung cancer samples (10 paired, 17 unpaired). APOBEC mutational signatures were more prevalent in receptor tyrosine kinase (RTK)-driven lung malignancies (EGFR, ALK, RET, and ROS1; 25%) compared to LUADs at large (20%, P<0.001); across all subtypes, APOBEC mutational signatures were enriched in subclonal mutations (P<0.001). In EGFR-mutant lung tumors, osimertinib-resistant samples more commonly revealed an APOBEC-dominant mutational signature compared to osimertinib-naïve samples (28% versus 14%, P=0.03). In particular, an APOBEC-dominant mutational signature was substantially more common in osimertinib-resistant tumors than in pre-treatment samples (44% versus 23%, P<0.001).
An enrichment of large-scale genomic rearrangements (P=0.01) and kataegis (P=0.03) in regions of APOBEC mutagenesis was found in EGFR-mutant samples with APOBEC-dominant signatures. APOBEC mutational signatures are widespread in RTK-driven LUADs and increase under the selective pressure of osimertinib in EGFR-mutant lung cancer. Subclonal mutations, individual mutations acquired after osimertinib treatment, and regions of large-scale genomic rearrangements are enriched for the APOBEC mutational signature, suggesting a possible central role for APOBEC mutagenesis in the emergence of resistance to targeted therapies that could be exploited to circumvent this resistance.