title: Mer receptor tyrosine kinase is frequently overexpressed in human non-small cell lung cancer, confirming resistance to erlotinib.
abstract: 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.
authors.affiliation: International Joint Cancer Institute, Second Military Medical University, Shanghai, China.|Department of Oncology, General Hospital of Chinese People's Armed Police Forces, Beijing, China.
authors.forename: Shengzhi
authors.initials: S
authors.lastname: Xie
authors.affiliation: Department of Radiology, 302 Hospital of Chinese People's Liberation Army, Beijing, China.
authors.forename: Yongwu
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Lung Cancer, Affiliated Hospital of Academy of Military Medical Sciences, Beijing, China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Li
authors.affiliation: Cancer Center Lab, Chinese People's Liberation Army General Hospital & Beijing Key Laboratory of Cell Engineering & Antibody, Beijing, China.
authors.forename: Linxiong
authors.initials: L
authors.lastname: Wang
authors.affiliation: South Building No. 2 Division, General Hospital of Chinese People's Armed Police Forces, Beijing, China.
authors.forename: Na
authors.initials: N
authors.lastname: Yang
authors.affiliation: International Joint Cancer Institute, Second Military Medical University, Shanghai, China.|Department of Radiation Oncology, General Hospital of Beijing Military Region, Beijing, China.
authors.forename: Yadi
authors.initials: Y
authors.lastname: Wang
authors.affiliation: International Joint Cancer Institute, Second Military Medical University, Shanghai, China.|Cancer Center Lab, Chinese People's Liberation Army General Hospital & Beijing Key Laboratory of Cell Engineering & Antibody, Beijing, China.
authors.forename: Huafeng
authors.initials: H
authors.lastname: Wei
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000473:pathology*; D002460:Cell Line; D002465:Cell Movement; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004847:Epithelial Cells / Q000378:metabolism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D000069347:Erlotinib Hydrochloride / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008168:Lung / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D020935:MAP Kinase Signaling System; D008297:Male; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D000076202:c-Mer Tyrosine Kinase
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors; C097072:MERTK protein, human; D020794:Receptor Protein-Tyrosine Kinases; D000076202:c-Mer Tyrosine Kinase
keywords: NSCLC; erlotinib; mer receptor tyrosine kinase; resistance; targeted therapy
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