Abstract 5251: Role of mammalian Hippo Mst1/2 protein kinase signaling in lung cancer progression.

Abstract

Abstract Lung cancer is the leading cause of cancer deaths worldwide. Non-small cell lung cancer (NSCLC) is a major lung adenocarcinoma observed in humans. Therapeutic options for patients with NSCLC are very limited and palliative since the disease mechanism is poorly understood. The Mst1/2 serine-threonine kinase, related to hippo (hpo) in drosophila, has emerged as an important regulator of tumorigenesis with poorer prognosis. However, the biological significance of Mst/Hippo in lung cancer pathogenesis remains to be determined. In this study, we assessed Mst1/2 expression at protein levels by western blots in cultures and in primary and metastatic lung cancer tissues by immunohistochemistry, and investigated the potential functional link between EGFR and Mst/Hippo signaling in well-characterized NSCLC cell models in vitro. We found that Mst1/2 protein levels were reduced by at least 50% in two out of five lung tumor cell lines analyzed. Surprisingly, reduction was observed in Erlotinib resistant H1734 and H1975 lung tumor cells. In agreement with this observation, Mst1 protein declined in primary lung tumor and was undetectable in metastatic lung cancer compared to non-cancerous counterparts. In addition, we showed that enforced Mst1 expression significantly increased sensitivity to EGFR inhibition by Erlotinib compared to mock treatment. We also showed that the activation of EGFR by epidermal growth factor (EGF) attenuated the Mst1 mediation of cell growth suppression. Taken together, our findings suggest that the loss of Mst/Hippo functions could contribute to lung tumor progression and acquired resistance to EGFR inhibitor. A molecular understanding of how these two opposing signals biochemically and functionally intersect may improve current EGFR blockade therapy. Citation Format: Bekir Cinar, Almet Alptekin, Ronald B. Natale. Role of mammalian Hippo Mst1/2 protein kinase signaling in lung cancer progression. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5251. doi:10.1158/1538-7445.AM2013-5251