APOBEC mutagenesis, kataegis, chromothripsis in EGFR-mutant osimertinib-resistant lung adenocarcinomas.

Selenica, P; Marra, A; Choudhury, N J; Gazzo, A; Falcon, C J; Patel, J; Pei, X; Zhu, Y; Ng, C K Y; Curry, M; Heller, G; Zhang, Y-K; Berger, M F; Ladanyi, M; Rudin, C M; Chandarlapaty, S; Lovly, C M; Reis-Filho, J S; Yu, H A (2022). APOBEC mutagenesis, kataegis, chromothripsis in EGFR-mutant osimertinib-resistant lung adenocarcinomas. Annals of oncology, 33(12), pp. 1284-1295. Oxford University Press 10.1016/j.annonc.2022.09.151

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BACKGROUND

Studies of targeted therapy resistance in lung cancer have primarily focused on single gene alterations. Based on prior work implicating APOBEC mutagenesis in histological transformation of EGFR-mutant lung cancers, we hypothesized that mutational signature analysis may help elucidate acquired resistance to targeted therapies.

PATIENTS AND METHODS

APOBEC mutational signatures derived from an FDA-cleared multigene panel (MSK-IMPACT) using the SigMA algorithm were validated against the gold standard of mutational signatures derived from whole exome sequencing. Mutational signatures were decomposed in 3,276 unique lung adenocarcinomas, including 93 paired osimertinib-naïve and resistant EGFR-mutant tumors. Associations between APOBEC and mechanisms of resistance to osimertinib were investigated. Whole-genome sequencing (WGS) was performed on available EGFR-mutant lung cancer samples (10 paired, 17 unpaired) to investigate large scale genomic alterations potentially contributing to osimertinib resistance.

RESULTS

APOBEC mutational signatures were more frequent in receptor tyrosine kinase (RTK)-driven lung cancers (EGFR, ALK, RET and ROS1; 25%) compared to lung adenocarcinomas at large (20%, p<0.001); across all subtypes, APOBEC mutational signatures were enriched in subclonal mutations (p<0.001). In EGFR-mutant lung cancers, osimertinib-resistant samples more frequently displayed an APOBEC dominant mutational signature compared to osimertinib-naïve samples (28 vs.14% p=0.03). Specifically, mutations detected in osimertinib-resistant tumors but not in pre-treatment samples significantly more frequently displayed an APOBEC dominant mutational signature (44% vs 23%, p<0.001). EGFR-mutant samples with APOBEC dominant signatures had enrichment of large scale-genomic rearrangements (p=0.01) and kataegis (p=0.03) in areas of APOBEC mutagenesis.

CONCLUSIONS

APOBEC mutational signatures are frequent in RTK-driven LUADs and increase under the selective pressure of osimertinib in EGFR-mutant lung cancer. APOBEC mutational signature enrichment in subclonal mutations, private mutations acquired after osimertinib treatment, and areas of large scale genomic rearrangements highlights a potentially fundamental role for APOBEC mutagenesis in the development of resistance to targeted therapies, which may be potentially exploited to overcome such resistance.

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