Abstract 3361: Surfaceome and cancer testis antigen profiling of lung adenocarcinoma by large-scale transcriptomic analysis

Abstract Background: The emergence of improved modalities to target tumor specific and tumor associated antigens in solid tumors (e.g. antibody-drug conjugates, bi-specific antibodies, and adoptive cell therapy) underscores the need to efficiently identify and validate new therapeutic targets. Methods: We examined differential expression of surfaceome genes (Fonseca et al., 2016) and cancer testis (CT) antigen genes (Almeida et al., 2009) among major lung adenocarcinoma genomic subtypes; conducting comprehensive surfaceome/CT antigen profiling of 9002 NSCLC adenocarcinoma samples using data generated by RNA sequencing (whole transcriptome) at Caris Life Sciences (Phoenix, AZ). NSCLC tumors were stratified into 5 subgroups based on the presence of specific driver mutations: ALK fusion (N=325), EGFR mutant (N=1739), KRAS mutant (no STK11 or KEAP1 mutation; N=2561), KRAS + STK or KEAP1 mutation (N=1264), and Pan-WT (no mutation in ALK, EGFR, KRAS, STK11, or KEAP1 detected; N=3113). Fold-change in expression was calculated by dividing the median value for a specific subgroup by the median of all other groups combined. Significance was tested by Mann-Whitney U test, with p-values adjust for multiple hypothesis testing (Benjamini-Hochberg). Results: Surfaceome genes with the highest median expression overall included CD74, TMBIM6, and CD44, while the highest median expression among CT antigens was observed for SPAG9, KIAA0100, and RQCD1, yet the expression of these genes across the 5 driver mutation-based subgroups was similar (fold-changes ranged 0.93-1.06). To identify driver-associated candidate genes with relatively high expression, genes with subgroup-specific median expression >75th-percentile and with significant differences when compared to all other groups were ranked by fold-change. While several candidate surfaceome genes were associated with a specific subgroup, CLDN10 was identified among the top 3 candidates for both ALK fusion and KRAS + STK11/KEAP1 mutant subgroups: ALK fusion (GRIN2A, 3.03-fold; CLDN10, 2.53-fold; SLITRK6, 1.86-fold), EGFR mutant (SFTPC, 3.82-fold; MUC21, 1.99-fold; ATP13A4, 1.60-fold), KRAS mutant (VSIG1, 1.86-fold; AREG, 1.47-fold; C15orf48, 1.25-fold), and KRAS + STK11/KEAP1 mutant (ABCC2, 4.03-fold; MUC13, 3.21-fold; CLDN10, 3.00-fold). The top driver-associated CT antigen candidates included LEMD1 (1.42-fold) in ALK fusion, TMEM108 (1.27-fold) in EGFR mutant, XAGE1D (1.7-fold) in KRAS mutant, and CABYR (1.52-fold) in KRAS + STK11/KEAP1 mutant subgroups. Conclusion: Our analysis revealed several surfaceome and CT antigen candidate genes with relatively high expression across lung adenocarcinoma, as well as differential expression of candidate genes within specific genomic subtypes. These findings can help prioritize the validation and development of novel therapeutic targets in lung adenocarcinoma. Citation Format: Swartz Andrew, Andrew Elliott, George W. Sledge, Stephen V. Liu, Balazs Halmos, Vincent K. Lam, Taofeek K. Owonikoko. Surfaceome and cancer testis antigen profiling of lung adenocarcinoma by large-scale transcriptomic analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3361.