Cancer esearch apeutics , Targets , and Chemical Biology l Surface Tetraspanin CD 9 Mediates Chemoresistance in R all Cell Lung Cancer

nloaded ll cell lung cancer (SCLC) is an aggressive malignancy with extremely high mortality due to the appearf widespread metastases early in its clinical course and rapid acquisition of chemoresistance after initial y. A theory of cell adhesion–mediated drug resistance is thought to be a principal mechanism in which ellular matrix proteins provide a survival advantage against cytotoxic drug-induced apoptosis. We found e tetraspanin family member CD9 was expressed preferentially in SCLC tumors and metastases from of seven relapsed patients, whereas chemonaïve primary tumors from 16 patients were CD9 negative nly one exception. Additionally, CD9 was highly expressed on SCLC cell lines rendered resistant to cisor etoposide, and was upregulated in parental chemosensitive cells within 48 hours after exposure to of these compounds. CD9-expressing chemoresistant SCLC cells adhered more tightly to fibronectin via egrin, but they were less motile than the respective chemosensitive parental lines. Notably, treatment of emoresistant cells with chemokine CXCL12 downregulated CD9 and transiently restored motility. Moreelective targeting of CD9 by treatment with specific monoclonal antibody ALB6 or a small interfering riggered apoptosis in the chemoresistant cells. Taken together, our findings implicate CD9 in the cell RNA t adhesion–mediated drug resistance mechanism, highlighting CD9 as an attractive therapeutic target to improve therapeutic outcomes in SCLC. Cancer Res; 70(20); 8025–35. ©2010 AACR.