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

Abstract

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.

• Authors: F Gelsomino, F Facchinetti, E R Haspinger, M C Garassino, L Trusolino, F De Braud, M Tiseo
• Journal: Critical reviews in oncology/hematology (Crit Rev Oncol Hematol) Vol. 89 Issue 2 Pg. 284-99 (Feb 2014) ISSN: 1879-0461 [Electronic] Netherlands
• PMID: 24355409 (Publication Type: Journal Article, Review)
• Copyright: Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents
• Protein Kinase Inhibitors
• ErbB Receptors
• Proto-Oncogene Proteins c-met

Topics

• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Carcinoma, Non-Small-Cell Lung (drug therapy, genetics, metabolism, pathology)
• Drug Resistance, Neoplasm
• ErbB Receptors (antagonists & inhibitors, metabolism)
• Humans
• Lung (drug effects, metabolism, pathology)
• Lung Neoplasms (drug therapy, genetics, metabolism, pathology)
• Molecular Targeted Therapy (methods)
• Protein Kinase Inhibitors (pharmacology, therapeutic use)
• Proto-Oncogene Proteins c-met (antagonists & inhibitors, genetics, metabolism)