ReviewMET/HGF targeted drugs as potential therapeutic strategies in non-small cell lung cancer
Graphical abstract
Introduction
Lung cancer is the tumor with the second highest incidence (≈14%) in both genders after prostate cancer in men and breast cancer in women [1]. According to the latest available statistics, more than 221,200 new cases are estimated for 2015 in the USA alone [1]. Lung cancer is also the first cause of death from cancer worldwide, with the prediction of 158,040 deaths in 2015 [1].
Non-small cell lung cancer (NSCLC) represents around 80% of lung cancer cases and is classified in three subtypes: adenocarcinoma, squamous cell (epidermoid) carcinoma, and large-cell carcinoma. Approximately 70% of NSCLC patients are diagnosed in an advanced stage (IIIB-IV), whose standard treatment, based on platinum chemotherapy [2], [3], [4], shows poor response rates (RR) of 17–32%, progression-free survival (PFS) of 3.1–3.5 months, and overall survival (OS) of 7.4–11.3 months [5], [6], [7], [8].
The biology and treatment of NSCLC has been revolutionized over the past few years due to the identification of druggable genetic alterations, such as epidermal growth factor receptor (EGFR) mutations or echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) translocations. EGFR is mutated in up to 59.7% of NSCLC tumors from Asian patients and in around 16.7% of those from Caucasian patients. EGFR mutations are more frequent in women and non-smokers [9], [10]. Most (90%) of the activating mutations correspond to leucine-to-arginine substitutions at position 858 (L858R) or deletions in exon 19, which affect the conserved sequence ELREA (delE746-A750). There have also been reports of a much less frequent mutation in exon 18, encompassing a substitution of glycine for alanine, cysteine or serine at codon 719 (G719X) [10], [11], [12], [13], [14], [15]. Novel therapeutic tyrosine kinase inhibitors (TKIs) targeted to these mutations, such as erlotinib (Tarceva®, Roche), gefitinib (Iressa®, AstraZeneca), or afatinib (Giotrif®, Boehringer Ingelheim), have shown RR of up to 75% [9], [16]. However, all patients with activating mutations in EGFR ultimately develop resistance to TKIs after a median of 12 months [10], [17], [18]. The most important resistance mechanism is a secondary point mutation in exon 20 of EGFR (T790 M), which replaces methionine with threonine at amino acid position 790. Other mechanisms reported in the literature include: MET protooncogen (MET) amplification and protein overexpression of its ligand, the hepatocyte growth factor (HGF); phosphatase and tensin homolog (PTEN) loss; kirsten rat sarcoma viral oncogene homolog (KRAS) mutations; v-raf murine sarcoma viral oncogene homolog B (BRAF) mutations; human EGF receptor 2 (HER-2) mutations, epithelial-to-mesenchymal transition (EMT); AXL receptor tyrosine kinase (AXL) overexpression; and small-cell transformation [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34].
Druggable alterations in NSCLC also include EML4-ALK translocations [35], [36], which have been reported in 3–7% of NSCLC patients, most frequently in younger patients with a history of no or light smoking and adenocarcinoma histology [37], [38]. Patients with this genetic alteration can benefit from crizotinib (Xalkori®, Pfizer), a potent TKI that is also active against MET and ROS1 (c-ROS oncogene) tyrosine kinases, which has shown overall response rates (ORR) of approximately 60% [39], [40] and PFS of 8–10 months [41]. As in the case of EGFR inhibitors, multiple resistance mechanisms have also been described, such as mutations in the ALK kinase domain (C1156Y, L1196M, G1296A) [42], [43], [44], [45], [46], [47], [48], [49].
The MET protooncogene encodes the c-Met protein, a tyrosine kinase receptor that binds to hepatocyte growth factor (HGF). Together with its ligand, c-Met plays a key role in several processes, such as proliferation, survival, motility, invasiveness, and stimulation of angiogenesis cell survival and proliferation through the PI3K/AKT, RAS-RAF-ERK1/2, and STAT3 pathways [50], [51], [52]. Alterations in the MET pathway, such as MET gene amplification and activating mutations or HGF overexpression, have been associated with a poor clinical outcome and EGFR-TKIs resistance in NSCLC patients [21], [32], [52], [53], [54], [55], [56] and MET inhibition is a promising strategy to overcome resistance to therapy in tumors with deregulated MET signaling [57].
Several MET inhibitors have been developed to block the HGF/MET signaling pathway (Fig. 1), including selective and non-selective MET TKIs, and monoclonal antibodies designed to prevent MET-HGF binding. Some of these inhibitors have been tested in clinical trials as single agents or in association with other targeted drugs, chemotherapy, or radiotherapy. In this review, we focus on these different strategies to prevent MET pathway activation.
Section snippets
MET pathway signaling and dysregulation
The MET tyrosine kinase (TK) receptor is a heterodimer that comprises an extracellular α-chain and transmembrane β-chain linked by a disulphide bond [58], [59]. The extracellular portion is constituted by a semaphorin (SEMA) domain, which is essential for ligand binding and receptor dimerization. A TK domain with four key tyrosine residues involved in MET pathway activation after HGF binding composes the intracellular portion, which is connected with the extracellular portion by juxtamembrane
MET: targeted drugs
Various clinical trials have tested molecules targeting HGF/MET signaling in treatment-naïve or TKI-resistant NSCLC patients [40], [97], [98], [105], [106], [107], [108], [109]. The results of some of those trials are already available and are summarized in Table 1, Table 2. Ongoing studies are reported in Table 3.
Conclusions
The stratification of NSCLC into different molecular subsets has revolutionized the treatment of this malignancy. It has led to the widespread clinical use of TKIs such as gefitinib and erlotinib (FDA-approved for patients with activating EGFR mutations) and crizotinib (FDA-approved for EML4-ALK translocated tumors). MET/HGF signaling also represents an important target in NSCLC. Through its activation of the PI3K/AKT, RAS-RAF-ERK1/2 and STAT3 pathways, MET plays a key role in several processes
Conflict of interest
The authors declare that there is not conflict of interest that could be perceived as prejudicing the impartiality of the research reported and there is not any competing financial interest in relation to the work described in this article.
Funding
This work was partly supported by a contract for Marisa Cañadas-Garre (Técnicos de Apoyo Subprogram. CA12/00097) from Instituto de Salud Carlos III, Ministerio de Economía y Competitividad and a research grant for Cristina Pérez-Ramírez (FPU12/04722), from Ministerio de Educación, Cultura y Deporte.
Acknowledgment
The results of this investigation are part of the doctoral thesis presented by Cristina Pérez-Ramírez at the University of Granada.
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