Investigation of the contribution of targeting exosome release to therapy in small cell LUNG cancers

Small cell lung cancer accounts for 15-20% of lung cancers. Small cell lung cancer (SCLC) is a tumor characterized by its early and distant metastasis ability, high proliferation capacity, low survival rates, and aggressive structure. The current treatment of SCLC uses cisplatin or platinum-derived compounds combined with etoposide. However, despite the basic and clinical research conducted over the past 30 years, no progress has been made in its treatment. Therefore, there is a necessity for new treatment strategies and new biomarkers to be discovered for the early diagnosis and treatment of SCLC. Extracellular vesicles called exosomes, which have been found to be constantly released by normal and cancerous cells in recent years, have been determined to play an important role in intercellular communication and the progression of various types of cancer. Various inhibitors have begun to be developed to target the biogenesis/release of these vesicles. In this study, the effects of targeting exosomes in SCLC treatment on SCLC carcinogenesis and the treatment process were investigated. Nexinhib20 and GW4869 inhibitors targeting Rab27a and nSMase, which play a role in exosome release, were used in the experiment. Administration of these inhibitors to SCLC cell lines N417 and H524 alone or in addition to existing therapy was determined by the cell proliferation assay and resulted in a significant reduction in cell proliferation rate (p< 0,0001). We observed that the use of inhibitors alone or in addition to existing therapy leads to a significant decrease in the number of exosomes released from SCLC cells. Additionally, the use of GW4869 and Nexinhib20 inhibitors in addition to the existing treatment caused SCLC cells to undergo apoptosis. As a result of the administration of GW4869 and Nexinhib20 alone or in combination, it was observed that the expression levels of cell cycle and exosome marker genes such as CD9, CD63, TSG101, Rab27A were found to be decreased (p< 0,0001). Our results revealed that exosomes have important roles in SCLC pathogenesis in vitro and targeting of RAB27A and nSMase genes in SCLC cell lines significantly reduces the activity of the exosomal pathway. Therefore, we believe that in addition to existing treatment strategies, the RAB27A and nSMase genes may be potential therapeutic targets in the treatment of SCLC.