Mer is a receptor tyrosine kinase (RTK) with oncogenic properties that is often overexpressed or activated in various malignancies.Using both immunohistochemistry and microarray analyses, we demonstrated that Mer was overexpressed in both tumoral and stromal compartments of about 70% of non-small cell lung cancer (NSCLC) samples relative to surrounding normal lung tissue.This was validated in freshly harvested NSCLC samples;however, no associations were found between Mer expression and patient features.Although Mer overexpression did not render normal lung epithelial cell tumorigenic in vivo, it promoted the in vitro cell proliferation,clonogenic colony formation and migration of normal lung epithelial cells as well as NSCLC cells primarily depending on MAPK and FAK signaling, respectively.Importantly, Mer overexpression induced resistance to erlotinib (EGFR inhibitor) in otherwise erlotinib-sensitive cells.Furthermore, Mer-specific inhibitor rendered erlotinib-resistant cells sensitive to erlotinib.We conclude that Mer enhances malignant phenotype and pharmacological inhibition of Mer overcomes resistance of NSCLC to EGFR-targeted agents.
mer receptor tyrosine kinase NSCLC targeted therapy erlotinib resistance
Shengzhi Xie Yongwu Li Xiaoyan Li Linxiong Wang Na Yang Yadi Wang Huafeng Wei
International Joint Cancer Institute,Second Military Medical University,Shanghai,China;Department of Department of Radiology,302 Hospital of Chinese People”s Liberation Army,Beijing,China Department of Lung Cancer,Affiliated Hospital of Academy of Military Medical Sciences,Beijing,China Cancer Center Lab,Chinese People”s Liberation Army General Hospital & Beijing Key Laboratory of Cell South Building No.2 Division,General Hospital of Chinese People”s Armed Police Forces,Beijing,China International Joint Cancer Institute,Second Military Medical University,Shanghai,China;Department of International Joint Cancer Institute,Second Military Medical University,Shanghai,China;Cancer Center