Abstract 5114: Investigating the novel role of the protease A Disintegrin And Metalloprotease (ADAM)-17 in small cell lung cancer

Abstract Lung cancer is the most lethal and common cancer worldwide, which comprises two main subtypes, non-small cell lung cancer and small cell lung cancer (SCLC), accounting for ∼85% and ∼15%, respectively, of all diagnoses. SCLC is a highly aggressive neuroendocrine malignancy which is detected in two thirds of SCLC patients at a late stage with a dismal 5-year survival rate of less than 5%. This poor outcome is largely due to the stagnated clinical management of SCLC over the last 3 decades, comprising first-line platinum-based chemotherapy with etoposide, which, despite initial high response rates, is associated with rapid disease relapse due to acquired chemoresistance. Therefore, there is a pressing clinical need to identity new molecular drivers of SCLC which can serve as therapeutic targets. In this regard, A Disintegrin And Metalloprotease 17 (ADAM17) is the major “sheddase” for >80 membrane-tethered pro-tumourigenic substrates, including epidermal growth factor receptor ligands, notch receptor and tumour necrosis factor-α, which control many cellular processes (e.g. inflammation, proliferation) in immune and non-immune cells. Therefore, ADAM17 modulates key physiological and pathophysiological cellular processes. Despite the large body of data implicating ADAM17 in lung cancer, the pathological role of ADAM17 in SCLC is unknown. Using our unique highly relevant and well-established clinical and preclinical models, including SCLC patient biopsies, the Rb1fl/fl;Trp53fl/fl (RP) and Rb1fl/flTrp53fl/flMycLSL/LSL (RPM) genetic mouse models, patient-derived xenografts and human SCLC cell lines, as well as proteomics pipeline and a suite of biochemical and molecular biology techniques, we aim to define the role of ADAM17 in SCLC. ADAM17 expression, interactome and substrate repertoire was investigated while the anticancer activity of ADAM17 inhibitors in SCLC was assessed. This research therefore could pave the way for the development of novel therapeutic and biomarker avenues for SCLC. Citation Format: Mohamed I. Saad, Karen Hon, Jelena Solujic, Teresa Weng, Arash Badiei, Clifford Young, Stefan Düsterhöft, Daniel Gough, Stefan Rose-John, Peter Hoffmann, Phan Nguyen, Brendan Jenkins. Investigating the novel role of the protease A Disintegrin And Metalloprotease (ADAM)-17 in small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5114.