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: Shengzhi Xie, Yongwu Li, Xiaoyan Li, Linxiong Wang, Na Yang, Yadi Wang, Huafeng Wei
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 11 Pg. 9206-19 (Apr 20 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 25826078 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Protein Kinase Inhibitors
• Proto-Oncogene Proteins
• Erlotinib Hydrochloride
• EGFR protein, human
• ErbB Receptors
• MERTK protein, human
• Receptor Protein-Tyrosine Kinases
• c-Mer Tyrosine Kinase

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Carcinoma, Non-Small-Cell Lung (drug therapy, pathology)
• Cell Line
• Cell Movement
• Cell Proliferation
• Drug Resistance, Neoplasm (drug effects)
• Epithelial Cells (metabolism)
• ErbB Receptors (antagonists & inhibitors)
• Erlotinib Hydrochloride (therapeutic use)
• Female
• Humans
• Lung (metabolism)
• Lung Neoplasms (drug therapy, pathology)
• MAP Kinase Signaling System
• Male
• Middle Aged
• Protein Kinase Inhibitors (pharmacology)
• Proto-Oncogene Proteins (antagonists & inhibitors, biosynthesis)
• Receptor Protein-Tyrosine Kinases (antagonists & inhibitors, biosynthesis)
• c-Mer Tyrosine Kinase