Journal
ANNALS OF ONCOLOGY
Volume 33, Issue 12, Pages 1284-1295Publisher
ELSEVIER
DOI: 10.1016/j.annonc.2022.09.151
Keywords
EGFR; mutational signatures; APOBEC; osimertinib; acquired resistance
Categories
Funding
- National Cancer Institute [NCI-P50CA247749, NCI-R01CA249666]
- EGFR Resisters/LUNGevity Lung Cancer Research Award
- GO2 Foundation ALK Positive Research Award [R01CA227833, P30-CA086485, UG1CA233259, P01CA129243]
- STARR foundation [R01CA264078]
- National Cancer Institute Cancer Center Core [P30-CA008748]
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This study found that APOBEC mutational signatures increase in EGFR-mutant lung cancer under the selective pressure of osimertinib. Samples with APOBEC mutational signatures had increased mutation frequency, more frequent occurrence of private mutations and large-scale genomic alterations.
Background: Studies of targeted therapy resistance in lung cancer have primarily focused on single-gene alterations. Based on prior work implicating apolipoprotein b mRNA-editing enzyme, catalytic polypeptide-like (APOBEC) mutagenesis in histological transformation of epidermal growth factor receptor (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 Food and Drug Administration-cleared multigene panel [Memorial Sloan Kettering Cancer Center Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT)] using the Signature Multivariate Analysis (SigMA) algorithm were validated against the gold standard of mutational signatures derived from whole-exome sequencing. Mutational signatures were decomposed in 3276 unique lung adenocarcinomas (LUADs), including 93 paired osimertinib-naive and -resistant EGFR-mutant tumors. Associations between APOBEC and mechanisms of resistance to osimertinib were investigated. Wholegenome sequencing was carried out 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 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 cancers, osimertinib-resistant samples more frequently displayed an APOBEC-dominant mutational signature compared to osimertinibnaive samples (28% versus 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% versus 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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