Mer receptor tyrosine kinase is frequently overexpressed in human non-small cell lung cancer, confirming resistance to erlotinib
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Shengzhi Xie1,2,*, Yongwu Li3,*, Xiaoyan Li4,*, Linxiong Wang5, Na Yang6, Yadi Wang1,7, Huafeng Wei1,5
1International Joint Cancer Institute, Second Military Medical University, Shanghai, China
2Department of Oncology, General Hospital of Chinese People’s Armed Police Forces, Beijing, China
3Department of Radiology, 302 Hospital of Chinese People’s Liberation Army, Beijing, China
4Department of Lung Cancer, Affiliated Hospital of Academy of Military Medical Sciences, Beijing, China
5Cancer Center Lab, Chinese People’s Liberation Army General Hospital & Beijing Key Laboratory of Cell Engineering & Antibody, Beijing, China
6South Building No. 2 Division, General Hospital of Chinese People’s Armed Police Forces, Beijing, China
7Department of Radiation Oncology, General Hospital of Beijing Military Region, Beijing, China
*These authors have contributed equally to this work
Huafeng Wei, e-mail: firstname.lastname@example.org
Yadi Wang, e-mail: email@example.com
Keywords: mer receptor tyrosine kinase, NSCLC, targeted therapy, erlotinib, resistance
Received: December 04, 2014 Accepted: February 07, 2015 Published: March 16, 2015
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.
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