Small cell lung cancer induced via non-canonical integrin-EGFR-KRAS activation

Lung cancer is the leading cause of cancer-related deaths worldwide. Small cell lung cancer (SCLC) is an extremely aggressive type of lung cancer with a patient median survival of 6-12 months. Epidermal growth factor (EGF) signaling plays an important role in triggering SCLC. Further, it has been reported that growth factor-dependent signals and alpha-, beta-integrin (ITGA, ITGB) heterodimer receptors functionally cooperate and integrate their signaling pathways. However, the precise role of integrins in EGF receptor (EGFR) activation in SCLC is unknown. In the present work we detected high ITGB2 and ITGA2 expression levels in SCLC by comparing RNA-sequencing data deposited at the European Genome-Phenome Archive and The Cancer Genome Atlas. Further experiments using retrospectively collected human lung tissue samples, human precision-cut lung slices (hPCLS) and cell lines confirmed these results and demonstrated that non-canonical ITGB2 signaling activates EGFR and RAS/MAPK/ERK signaling in SCLC.