Neuropeptide bombesin receptor activation stimulates growth of lung cancer cells through HER3 with a MAPK-dependent mechanism

Abstract

Despite recent advances in treatment of non-small cell lung cancer (NSCLC), prognosis still remains poor and new therapeutic approaches are needed. Studies demonstrate the importance of the EGFR/HER-receptor family in NSCLC growth, as well as that of other tumors. Recently, HER3 is receiving increased attention because of its role in drug resistance and aggressive growth. Activation of overexpressed G-protein-coupled receptors (GPCR) can also initiate growth by transactivating EGFR/HER-family members. GPCR transactivation of EGFR has been extensively studied, but little is known of its ability to transactivate other EGFR/HER-members, especially HER3. To address this, we studied the ability of bombesin receptor (BnR) activation to transactivate all EGFR/HER-family members and their principal downstream signaling cascades, the PI3K/Akt- and MAPK/ERK-pathways, in human NSCLC cell-lines. In all three cell-lines studied, which possessed EGFR, HER2 and HER3, Bn rapidly transactivated EGFR, HER2 and HER3, as well as Akt and ERK. Immunoprecipitation studies revealed Bn-induced formation of both HER3/EGFR- and HER3/HER2-heterodimers. Specific EGFR/HER3 antibodies or siRNA-knockdown of EGFR and HER3, demonstrated Bn-stimulated activation of EGFR/HER members is initially through HER3, not EGFR. In addition, specific inhibition of HER3, HER2 or MAPK, abolished Bn-stimulated cell-growth, while neither EGFR nor Akt inhibition had an effect. These results show HER3 transactivation mediates all growth effects of BnR activation through MAPK. These results raise the possibility that targeting HER3 alone or with GPCR activation and its signal cascades, may be a novel therapeutic approach in NSCLC. This is especially relevant with the recent development of HER3-blocking antibodies.