Abstract 1374: Small cell lung cancer predominantly expressing ASCL1 shows a distinct oxidative phenotype
Authors: Schelch Karin , Schwendenwein Anna , Boettiger Kristiina , Kirchhofer Dominik , Lang Christian , Megyesfalvi Zsolt , Szeitz Beata , Hoetzenecker Konrad , Unger Lukas , Rezeli Melinda , Dome Balazs 
Published: June 2023

Abstract
Small cell lung cancer (SCLC) accounts for approximately 15% of lung cancers and has a poor prognosis due to a high proliferation rate and early metastasis. The current standard treatment, a combination of a platinum-based chemotherapy and etoposide, does not consider the underlying molecular profiles and, therefore, displays limited success. Tailoring treatment to the specific attributes of the 4 SCLC subtypes characterized by the predominant expression of either ASCL1, NeuroD1, POU2F3 or YAP1 (SCLC-A/N/P/Y) might improve patient outcomes. Here, we investigated the proteomic landscape of SCLC subsets with the aim to identify novel subtype-specific characteristics of diagnostic and therapeutic relevance. MS-based proteomics on 26 human SCLC cell lines was performed to decipher pathway-level differences between the subtypes. Mitochondria and lipid droplets were stained with Mitotracker Red CMXROS and Bodipy 493/503, respectively, and quantified by flow cytometry and confocal imaging. Differential responses to inhibitors of complex 1 (metformin, IACS-010759), the CPT1 inhibitor perhexiline, the glutaminolysis inhibitor BPTES and the aerobic glycolysis inhibitor UK5099 were tested using MTT-based cell viability assays. Pathway analyses based on proteomic data identified several metabolic pathways including “oxidative phosphorylation” (OXPHOS) to be significantly upregulated in SCLC-A compared to the other subtypes. Furthermore, multiple proteins essential for the electron transport chain (COX4I1, COX5B, NDUFA5) were highly expressed. Analysis of mitochondria showed a significantly higher number of mitochondria in cells (n=3) from the SCLC-A subtype, which also exhibited a more elongated shape. Lipid droplets were more abundant in the other, low OXPHOS subtypes (n=3). Perhexiline treatment confirmed higher OXPHOS activity solely in the SCLC-A subtype. In contrast, low OXPHOS cells were more sensitive to glutaminolysis inhibition, while no difference was seen when glycolysis was inhibited. Suggesting a differential response to clinically used OXPHOS inhibitors, SCLC cell lines with high and low oxidative activity were treated with metformin and IACS-010759 and response to treatment correlated positively with oxidative state. In this study, we demonstrate distinct differences in metabolic processes in the SCLC-A subtype compared to the other subtypes. Specifically, our data show upregulated oxidative phosphorylation as a potential therapeutic target. Understanding the variances in the metabolic phenotype between the molecular subtypes is integral to achieving precision medicine and advancing SCLC patient treatment.
Citation Format: Karin Schelch, Anna Schwendenwein, Kristiina Boettiger, Dominik Kirchhofer, Christian Lang, Zsolt Megyesfalvi, Beata Szeitz, Konrad Hoetzenecker, Lukas Unger, Melinda Rezeli, Balazs Dome. Small cell lung cancer predominantly expressing ASCL1 shows a distinct oxidative phenotype [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 1374.