The Role of MET Receptor Tyrosine Kinase in Non-Small Cell Lung Cancer and Clinical Development of Targeted Anti-MET Agents

Abstract

A better understanding of the pathophysiology and evolution of non-small cell lung cancer (NSCLC) has identified a number of molecular targets and spurred development of novel targeted therapeutic agents. The MET receptor tyrosine kinase and its ligand hepatocyte growth factor (HGF) are implicated in tumor cell proliferation, migration, invasion, and angiogenesis in a broad spectrum of human cancers, including NSCLC. Amplification of MET has been reported in approximately 5%-22% of lung tumors with acquired resistance to small-molecule inhibitors of the epidermal growth factor receptor (EGFR). Implications for Practice: Identification of the role of the HGF-MET pathway in cancer, and specifically in non-small cell lung cancer (NSCLC) has led to the development of pharmaceutical agents targeting this pathway. In particular, MET's role in secondary resistance to EGFR-directed therapies has led to the investigation of combining MET-directed agents with erlotinib in patients with metastatic NSCLC. This article reviews the early development of MET-directed therapies as well as currently ongoing Phase III studies.We await the results of these studies, which will determine whether targeting MET in combination with EGFR is a valid clinical option in patients whose cancers progress following treatment with EGFR inhibitors.

MET Amplification Status in Therapy-Naïve Adeno- and Squamous Cell Carcinomas of the Lung

“…Better understanding of the molecular pathophysiology of non-small cell lung cancer (NSCLC) has led to the development of more selective and targeted treatment options with improved outcome rates (2,3). With the discovery of EGFR mutations, EML4-ALK (Echinoderm microtubule-associated protein like 4-anaplastic lymphoma kinase) translocations and the ROS1 translocation, lung cancer treatment has been fundamentally changed and shown to be much more effective than ancient chemoradiation therapy regimens (4)(5)(6)(7).…”

“…MET is a heterodimeric transmembrane receptor tyrosine kinase, composed of an extracellular a-chain and a transmembrane spanning b-chain linked via disulfide bonds (2) and its gene is localized to chromosome 7q (8). Binding of HGF to MET triggers receptor dimerization and transphosphorylation, which lead to conformational changes of the receptor with subsequent activation of the tyrosine kinase (TK).…”

An Improved Procedure for the Preparation of Poziotinib

“…In particular, activating mutations such as the L858R point mutation in exon 21 and the small inframe deletions in exon 19 of the EGFR tyrosine kinase domain are correlated with sensitivity to EGFR tyrosine kinase inhibitors in non-small cell lung cancer (NSCLC) patients [1][2][3][4]. Poziotinib 1, a highly potent, and orally bioavailable inhibitor of human epidermal growth factor receptors HER 1 , HER 2 , and HER 4 tyrosine kinase, was developed in a late-stage clinic trial for the prevention and treatment of patients with NSCLC including clinical limitation caused by acquired mutation (EGFR T790M), breast cancer and gastric cancer by Hanmi Science Co., Ltd [5][6][7]. It could be marketed for the treatment of advanced solid tumors as a new-generation anticancer.…”

“…1 H-NMR (DMSO-d 6 Preparation of tert-butyl l-4-(4-(3,4-dichloro-2-fluorophenylamino)-7-methoxyquinazolin-6-yloxy) piperidin-l-carboxylate (6) 4-(3,4-dichloro-2-fluorophenylamino)-7-methoxyquinazolin-6-ol (12.6 g, 0.036mol) was admixed with N,N-dimethylformamide (80 ml) under stirring, followed by addition of tert-butyl 4-(tosyloxy)piperidin-l-carboxylate (15 g, 0.042 mol) and potassium carbonate (15 g, 0.113) to the mixture. The reaction temperature was raised to 90 °C, and the mixture was stirred for 3 hours(TLC monitor).…”

Development of a Novel c-MET–Based CTC Detection Platform

“…Although best described in gastroesophageal tumors (16,17), MET gene amplification can occur in several other malignancies, including NSCLC (18), ovarian cancer (19), and colorectal cancer (20), particularly as a mechanism of resistance to therapies targeting EGFR (e.g., cetuximab in colorectal cancer and gefitinib in NSCLC; refs. 20,21).…”