MicroRNA-200a Targets EGFR and c-Met to Inhibit Migration, Invasion, and Gefitinib Resistance in Non-Small Cell Lung Cancer.

Lung cancer, especially non-small cell lung cancer (NSCLC), is the major cause of cancer death worldwide. Mutations in epidermal growth factor receptor (EGFR) and hepatocyte growth factor receptor (c-Met), both of which are receptor tyrosine kinases, have been identified in a considerable percentage of NSCLC patients. EGFR and c-Met share the same downstream pathways and cooperate not only in promoting metastasis but also in conferring resistance to tyrosine kinase inhibitor (TKI) therapies in NSCLC. MicroRNAs (miRNAs) are a family of small non-coding RNAs, usually 21-25 nucleotides long, and are critical in regulating gene expression. Abnormal miRNA expression has been implicated in the initiation and progression in many forms of cancers, including lung cancer. In this study, we found that miR-200a is downregulated in NSCLC cells, where it directly targets the 3'-UTR of both EGFR and c-Met mRNA. Overexpression of miR-200a in NSCLC cells significantly downregulates both EGFR and c-Met levels and severely inhibits cell migration and invasion. Moreover, in NSCLC cell lines that are resistant to gefitinib, a drug often used in TKI therapies to treat NSCLC, miR-200a expression is able to render the cells much more sensitive to the drug treatment.

Zhen Q ，Liu J ，Gao L ，Liu J ，Wang R ，Chu W ，Zhang Y ，Tan G ，Zhao X ，Lv B ... -  《-》

MicroRNA-34a overcomes HGF-mediated gefitinib resistance in EGFR mutant lung cancer cells partly by targeting MET.

Zhou JY ，Chen X ，Zhao J ，Bao Z ，Chen X ，Zhang P ，Liu ZF ，Zhou JY ... -  《-》

The role of MET activation in determining the sensitivity to epidermal growth factor receptor tyrosine kinase inhibitors.

Rho JK ，Choi YJ ，Lee JK ，Ryoo BY ，Na II ，Yang SH ，Lee SS ，Kim CH ，Yoo YD ，Lee JC ... -  《-》

MicroRNA-133b inhibits the growth of non-small-cell lung cancer by targeting the epidermal growth factor receptor.

Both the deregulation of microRNAs and epidermal growth factor receptor (EGFR) are emerging as important factors in non-small-cell lung cancer (NSCLC). Here, miR-133b was found to be associated with tumor stage, the extent of regional lymph node involvement, stage, visceral pleura or vessel invasion and EGFR mRNA expression in Chinese patients with NSCLC. Bioinformatic analysis and luciferase reporter assay revealed that miR-133b can interact specifically with the 3'-UTR of EGFR mRNA. Functionally, miR-133b transfection showed regulatory activity in translationally repressing EGFR mRNA. Moreover, miR-133b transfection may modulate apoptosis, invasion and sensitivity to EGFR-TKI through the EGFR signaling pathways, especially in EGFR-addicted NSCLC cells. Taken together, our findings show that miR-133b can inhibit cell growth of NSCLC through targeting EGFR and regulating its downstream signaling pathway. This finding has important implications for the development of targeted therapeutics for a number of EGFR-addicted cancers.

Liu L ，Shao X ，Gao W ，Zhang Z ，Liu P ，Wang R ，Huang P ，Yin Y ，Shu Y ... -  《-》

Targeting the MET gene for the treatment of non-small-cell lung cancer.

Recently, a better understanding of the specific mechanisms of oncogene addiction has led to the development of antitumor strategies aimed at blocking these abnormalities in different malignancies, including lung cancer. These abnormalities trigger constitutive activation of tyrosine kinase receptors (RTKs) involved in fundamental cell mechanisms such as proliferation, survival, differentiation and migration, and consequently the aberrant signaling of RTKs leads to cancer growth and survival. The inhibition of aberrant RTKs and downstream signaling pathways has opened the door to the targeted therapy era. In non-small-cell lung cancer (NSCLC), molecular research has allowed the discrimination of different aberrant RTKs in lung cancer tumorigenesis and progression, and thus the identification of several targetable oncogenic drivers. Following the development of small molecules (gefitinib/erlotinib and crizotinib) able to reversibly inhibit the epidermal growth factor receptor (EGFR) and signaling pathways mediated by anaplastic lymphoma kinase (ALK), respectively, the MET signaling pathway has also been recognized as a potential target. Moreover, according to current knowledge, MET could be considered both as a secondary oncogenic mechanism and as a prognostic factor. Several therapeutic strategies for inhibiting activated hepatocyte growth factor receptor (HGFR) and the subsequent downstream signaling transduction have been improved in order to block tumor growth. This review will focus on the MET pathway and its role in resistance to EGFR TK (tyrosine kinase) inhibitors, the different strategies of its inhibition, and the potential approaches to overcoming acquired resistance.

Gelsomino F ，Facchinetti F ，Haspinger ER ，Garassino MC ，Trusolino L ，De Braud F ，Tiseo M ... -  《-》