Somatostatin receptor 2 signaling promotes growth and tumor survival in small‐cell lung cancer. Issue 5 (9th October 2018) - Lehman, Jonathan M.
Abstract : Somatostatin receptor 2 (SSTR2) is overexpressed in a majority of neuroendocrine neoplasms, including small‐cell lung carcinomas (SCLCs). SSTR2 was previously considered an inhibitory receptor on cell growth, but its agonists had poor clinical responses in multiple clinical trials. The role of this receptor as a potential therapeutic target in lung cancer merits further investigation. We evaluated the expression of SSTR2 in a cohort of 96 primary tumors from patients with SCLC and found 48% expressed SSTR2. Correlation analysis in both CCLE and an SCLC RNAseq cohort confirmed high‐level expression and identified an association between NEUROD1 and SSTR2. There was a significant association with SSTR2 expression profile and poor clinical outcome. We tested whether SSTR2 expression might contribute to tumor progression through activation of downstream signaling pathways, using in vitro and in vivo systems and downregulated SSTR2 expression in lung cancer cells by shRNA. SSTR2 downregulation led to increased apoptosis and dramatically decreased tumor growth in vitro and in vivo in multiple cell lines with decreased AMPKα phosphorylation and increased oxidative metabolism. These results demonstrate a role for SSTR2 signaling in SCLC and suggest that SSTR2 is a poor prognostic biomarker in SCLC and potential future therapeutic signaling target. Abstract : What's new? Small‐cell lung cancer (SCLC) is a highly aggressive and metastatic neuroendocrine carcinoma with no therapeutic improvement in decades. SSTR2 is canonically viewed as an inhibitory receptor on cell growth, but trials have shown poor clinical responses to agonists. This work shows that SCLC cell lines and primary tumors express high levels of SSTR2, and high SSTR2 expression is correlated with worse patient survival in SCLC. Furthermore, SSTR2 signaling rather serves as an important protumor survival signal in a subset of SCLC cell lines/tumor tissues, with loss of SSTR2 expression leading to profound effects on apoptosis with significant clinical implications.