Developing c-MET pathway inhibitors for cancer therapy: progress and challenges

Successfully developed target-based therapies have significantly changed cancer treatment. Among many targets, the c-MET receptor tyrosine kinase and its ligand hepatocyte growth factor have recently gained considerable attention. The c-MET pathway is dysregulated in most human malignancies, and regulates tumor formation, progression and dissemination, and numerous c-MET pathway inhibitors are currently being evaluated in the clinic. Although some studies have shown impressive evidence of antitumor activity, the data should be interpreted with caution because of the distinct properties of these agents and diverse patient populations studied. Furthermore, in tumor types where patients might benefit from c-MET inhibition, rational combination treatments might ultimately provide maximal clinical benefit. Here, we review the evidence linking c-MET activation to cancer, and discuss the latest progress, opportunities and challenges in the clinical development of c-MET pathway inhibitors.

Introduction

Significant progress has been made towards developing target-based cancer therapies over the past decade. Numerous agents have been approved that are designed to block specific signaling pathways important for tumor formation, progression, dissemination and/or angiogenesis [1]. Despite the remarkable success, most approved agents do not cure patients. In addition, pre-existing resistance to these agents is readily detectable in many intent-to-treat (ITT) patients. Furthermore, most patients who initially respond to the treatments nevertheless develop resistance, and the tumors that emerge are often more aggressive and difficult to treat. Although mechanisms for resistance might vary, one major problem is the extremely complex nature of tumor cells because of their genetic heterogeneity and instability. Recent genomic and biochemical studies indicate that even in tumors of the same tissue origin there are many differences that potentially contribute to the disease 2, 3. Thus, the ultimate success in controlling most if not all cancers requires the application of multiple agents that effectively inhibit different pro-cancer mechanisms.

Oncogenic protein kinases represent a class of biologically important targets for cancer intervention. Among them, c-MET and its ligand hepatocyte growth factor (HGF) have recently attracted considerable attention. c-MET belongs to a subfamily of receptor tyrosine kinases (RTKs), which also includes RON and SEA [4]. HGF is the only known high affinity ligand for c-MET. The mature c-MET receptor is structurally distinct from most other RTKs and exists as a heterodimer containing an extracellular α chain and a transmembrane β chain, which anchors the kinase domain in its cytoplasmic portion (Figure 1). Detailed descriptions of the structural domains and their functions with respect to c-MET and HGF can be found elsewhere 4, 5, 6.

In normal physiology, the c-MET pathway regulates many cellular responses including cell proliferation, survival, motility, invasion and morphogenesis 4, 6. Upon activation via HGF binding and/or receptor overexpression, c-MET autophosphorylates, recruits adaptor proteins and activates multiple downstream effector proteins and cascades, as illustrated in Figure 1. The participation of these adaptors and effectors is essential for c-MET to exert its full biological functions [7]. HGF and c-MET are expressed in various tissues, but are usually restricted to cells of epithelial and mesenchymal origin 4, 6. Mouse genetic studies support the essential roles of both HGF and c-MET in normal embryonic development and organogenesis [4]. The functions of HGF and c-MET in adults, however, are more restricted, and are involved mainly in tissue damage repair and regeneration 4, 5, 8.

Since the discovery of c-MET and HGF, much research interest has focused on their roles in cancer. The c-MET pathway is one of the most frequently dysregulated pathways in human cancer, and aberrant c-MET signaling has been documented in most solid tumors and hematological malignancies 4, 6. The strongest evidence that links c-MET directly to cancer came from the original discovery of missense c-MET mutations in all patients with hereditary papillary renal cell carcinomas (PRCC) and a small subset (13%) of sporadic PRCC samples 4, 6. Trisomy of chromosome 7, where both HGF and c-MET genes are located, also occurs frequently in PRCC. Subsequently, c-MET mutations were reported in many other cancers, including gastric, head and neck, liver, ovarian, non-small cell lung (NSCL) and thyroid cancers, as well as in metastases of some of these cancers 6, 7, 9. The tumorigenic potential of several c-MET mutants was confirmed in preclinical models 10, 11. In addition, c-MET is also commonly activated via receptor overexpression and amplification, as well as by elevated HGF levels. c-MET has been shown to be frequently overexpressed or amplified in many cancers, including brain, colorectal, gastric, lung, head and neck and stomach cancers 6, 7, 12, 13, 14, and circulating HGF levels are elevated in most cancers 4, 15, 16. Both amplifications have been associated with poor clinical outcomes 6, 7, 14, 15, 16, 17, 18, 19, underscoring the importance of increased c-MET signaling in these cancer types.

The involvement of HGF/c-MET in cancer has also been supported by more recent data. For instance, a somatic mutation/polymorphism in the HGF promoter region, which results in increased HGF expression, was recently identified in breast cancer patients, with significant prevalence in patients of African American (51%) and European descent (15%) [20]. Moreover, individuals carrying the mutation are substantially younger and present with a more aggressive disease, underscoring its potential as a genetic marker for identifying high risk individuals. Upon careful examination of tumor biopsies, it was also found that not only is c-MET expressed in solid tumors, but HGF is widely detected in the intratumoral spaces of solid tumors, indicating a potential role of an HGF autocrine/paracrine loop in solid tumors [21]. In addition, the recent identification of upregulated metastasis-associated in colon cancer-1 (MACC1), which plays a crucial role in promoting tumor metastasis by controlling c-MET transcription, further supports the role of c-MET in colon cancer [22].

c-MET signaling can also be modulated by other proteins/enzymes, including RON, EGFRs, α6β4 integrin, plexin B1, CD44 and FAS (Figure 1) 6, 7, 23. The interactive relationships between c-MET and these proteins have been corroborated by numerous studies either on an individual protein basis or a systematic, global scale 7, 24. Although the exact mechanisms are still under investigation, the complex network in which the c-MET receptor interacts with these proteins, many of which are known to have important roles in cancer, is further evidence that the HGF/c-MET axis is a key regulator in cancer.

An activated c-MET promotes tumor cell growth, survival, migration and invasion, as well as tumor angiogenesis 4, 6, 25. The historical evidence that validates the c-MET pathway as a cancer target mainly comes from the data generated by two complementary approaches. First, the overexpression of HGF and/or c-MET (wild type or mutants) confers a transforming phenotype in cell lines, whereas mice expressing HGF and/or c-MET as a transgene(s) develop different tumors and metastatic lesions 4, 6. Second, the downregulation of HGF or c-MET expression or inhibition of c-MET kinase in HGF/c-MET-driven tumor cells significantly decreases cell growth, survival, motility, migration and invasion in vitro, and reduces tumorigenic and metastatic potential in vivo 6, 7. Recent studies using pharmaceutically-developed monoclonal antibodies (mAbs) and small molecule c-MET tyrosine kinase inhibitors (TKIs) further support the therapeutic potential of c-MET inhibition, as we will discuss in greater detail.

In summary, the c-MET pathway has been strongly implicated in a variety of human malignancies. The preclinical data that support therapeutic approaches for c-MET inhibition in cancer are both extensive and convincing, offering a compelling rationale for the further exploration of targeting c-MET in patients.