Abstract 6029: Multi-omic landscape of squamous cell lung cancer

Abstract

Abstract Patients with squamous cell lung cancer (SCC) have high unmet medical need. Knowledge of these tumors is limited, and a lack of targetable genomic drivers means patients have few treatment options. To provide a detailed analysis on the influence of genomic alterations to proteome-level changes in SCC, we previously integrated DNA copy number, somatic mutations, RNA-sequencing, and expression proteomics in a cohort of 108 SCC patients. A major finding was identification of three proteomic subtypes, two of which made up the majority (87%) of tumors: the “Inflamed” subtype was enriched for B-cell rich tertiary lymphoid structures (TLS), and the “Redox” subtype was enriched for redox pathways and NFE2L2/KEAP1 alterations but had significantly less immune infiltration. We hypothesized these proteomic subtypes would give rise to distinct metabolic signatures. Therefore, we performed untargeted metabolomics on 87 tumors from the same cohort using chromatographic separation on a HILIC column, followed by analysis on a Q Exactive HF mass spectrometer. This analysis yielded 7,344 features corresponding to 7,072 unannotated metabolites and 272 identified metabolites. Glutathione, a key redox metabolite, was anticorrelated with immune score (R = -0.44, padj = 0.004) calculated from our transcriptomic data with the ESTIMATE algorithm, and glutathione was elevated in the Redox proteomic subtype (0.58 log2 ratio, padj = 9.87E-04). Consensus clustering was next used to identify novel metabolomic subtypes of SCC. Surprisingly, none of the five metabolomic subtypes we identified corresponded to proteomic subtype or NFE2L2/KEAP1 alteration (Fisher’s Exact test p-values > 0.05). The fifth subtype had 332 metabolites (26 identified) differentially expressed (> 1.5 fold-change, padj < 0.05) with ascorbate and aldarate metabolism as the top enriched pathway (padj = 3.36E-04). Interestingly, this fifth metabolomic subtype had significantly higher DNp63-alpha (p = 2.40E-05), a primary transcript of delta-N p63 that is known to promote non-small cell lung cancer. Ongoing integrative analyses across omic types will determine how p53, p63, and p73 transcripts influence these metabolomic subtypes, how these transcripts relate to the poor immune infiltration in some SCC tumors, and if these transcripts relate to novel metabolic vulnerabilities in SCC. Citation Format: Paul Stewart, Ashley Lui, Eric Welsh, Dalia Ercan, Vanessa Rubio, Hayley Ackerman, Guohui Li, Bin Fang, Steven Eschrich, John Koomen, Elsa Flores, Eric Haura, Gina DeNicola. Multi-omic landscape of squamous cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6029.