Anti-MET-targeted therapy for NSCLC: has it come of age?

Abstract

Lung cancer molecular-targeted therapy has made its way into the standard of care in clinical cancer therapy in recent years. Recent clinical data also provided strong rationale for the first-line use of small molecular inhibitors against EGFR, gefitinib or erlotinib, in non-small-cell lung cancer (NSCLC) patients harboring EGFR-TKIsensitizing mutations [1]. Molecularly matched targeted therapy represents a newly emerged paradigm that is founded upon the concept of ‘oncogene addiction’. This paradigm is further consolidated by the successful development and now clinically approved use of crizotinib, a dual ALK and MET inhibitor, in NSCLC expressing the ALK 2p23 fusion oncogenic rearrangement as in EML4-ALK. Nonetheless, both EGFR and ALK inhibitors only target relatively small fractions of the NSCLC population, and resistance inevitably developed despite initial responses [2,3]. Further novel targeted-therapy development clearly remains a top priority to impact lung cancer. Of interest is that crizotinib was initially developed in preclinical studies and in the initial Phase I study to be a MET receptor-kinase inhibitor, but was promptly shifted into being developed as an ALK-targeted therapeutic, and successfully so, after the discovery of EML4-ALK in NSCLC [4]. MET signaling cascade plays key roles in developmental signaling regulation in embryogenesis and early development. By contrast, MET signaling in adult tissues is typically in quiescence physiologically, except in processes of homeostasis such as wound healing. In human cancers, a dysregulated MET pathway is very commonly involved in tumorigenesis, tumor invasion and progression, and tumor metastasis [5,6]. MET, along with its specific natural ligand HGF (also called scatter factor), has been under extensive preclinical investigation for over 25 years. The MET/HGF signaling axis is now recognized as a ‘druggable target’ and is included as one of the ‘hallmarks of cancer’ [7] based on its role in “activating invasion and metastasis” [6]. The first selective preclinical MET inhibitors, SU11274 and PHA665752, used to validate MET targeting therapy in lung cancer, were reported back in 2003–2005 [8–10]. Currently, there are many experimental therapeutic agents targeting against MET and HGF that are already under clinical development in various phases in multiple cancer types. As the therapeutic target, MET receptor protein overexpression can activate the signaling pathway via transcriptional activation (e.g., through hypoxia), genomic amplification, or downregulated receptor proteolysis (e.g., through juxtamembrane CBL-binding domain mutation).