Proteogenomic characterization of antibody-drug conjugate target expression profiles in transcriptional subtypes of small cell lung cancer.

e20113 Background: Small cell lung cancer (SCLC) is a highly lethal malignancy, and there is an urgent need for more effective therapies. Antibody-drug conjugates (ADCs), which combine the precision of monoclonal antibodies with the cytotoxic power of small molecules, represent a promising approach. Despite extensive research, the relationship between ADC target overexpression and the transcriptional profile of SCLC remains unclear. Our study aimed to elucidate how ADC target expression correlates with transcriptional subtypes of SCLC, potentially guiding the selection of ADCs based on molecular profiling. Methods: RNA-seq and tandem mass spectrometry data for 107 patients with matched SCLC tumors and normal adjacent lung tissue were obtained from the CPTAC SCLC cohort. SCLC subtypes were defined according to expression of four transcription factors: achaete-scute homologue 1 (ASCL1), neurogenic differentiation factor 1 (NeuroD1), yes-associated protein 1 (YAP1) and POU class 2 homeobox 3 (POU2F3). ADC target expression for DLL3, SEZ6, B7-H3 ( CD276 ), and Trop2 ( TACSTD2 ) were assessed at the transcriptomic and proteomic level. The correlation between transcriptional subtype and ADC target expression was determined using Pearson’s correlation coefficient. Results: In 107 SCLC tumors, subtypes corresponded to 66 (61.6%) ASCL1, 21 (19.6%) NeuroD1, 3 (2.8%) YAP1, and 17 (15.9%) POU2F3. The ASCL1 subtype was positively correlated with DLL3 (R 2 =0.93, p=9E-87) and SEZ6 (R 2 =0.85, p=2.9E-57), and negatively correlated with TROP2 expression (R 2 =-0.72, p=1.5E-34). The NEUROD1 subtype showed moderate positive correlation with DLL3 (R 2 =0.52, p=4.8E-14) and SEZ6 (R 2 =0.58, p=3.6E-18), and a moderate negative correlation with TROP2 (R 2 =-0.52, p=1.6E-14). The POU2F3 subtype did not demonstrate strong positive or negative correlations with ADC targets. The YAP1 subtype was negatively correlated DLL3 (R 2 =-0.72, p=1.1E-32) and SEZ6 (R 2 =-0.71, p=9.5E-33), and positively correlated with Trop2 expression (R 2 =0.85, P=7.5E-61). Conclusions: Our findings reveal that molecular subtypes of SCLC exhibit unique patterns of ADC target expression. These profiles are crucial for further research and could lead to the development of subtype-specific treatments that improve clinical outcomes for patients with SCLC.