Activation of the HIF pathway in cancer

Inhibiting c-MET (mesenchymal_epithelial transition factor) signaling is emerging as a promising strategy for a new class of targeted cancer therapies. Several c-MET inhibitors are in various stages of clinical development and have demonstrated activity in different tumor HIF pathway types. c-MET is a receptor tyrosine kinase encoded by the proto-oncogene MET and has a high affinity for hepatocyte growth factor (HGF; also known as scatter factor, SF) [Cooper et al. 1984]. Activation of c-MET, mediated by HGF binding, promotes several processes involved in oncogenesis, including tumor cell proliferation, migration, invasion, angiogenesis, protection from apoptosis and metastasis, working through several other signaling pathways such as PI3K/Akt, Src, STAT3, and Ras/Mek [Comoglio et al. 2008; Zhang et al.
2003; Trusolino and Comoglio, 2002; Furge et al. 2000]. The c-MET pathway is frequently survivin dysregulated in human cancers, and aberrant c-MET signaling has been reported in a wide variety of human malignancies, including gastric, lung, colon, breast, bladder, head and neck, ovarian, prostate, thyroid and pancreatic as well as hematologic malignancies and central nervous system tumors [Liu et al. 2008; Birchmeier et al. 2003; Di Renzo et al. 2000; Ferracini et al. 1995]. Oncogenic activation of c-MET signaling can be induced by specific genetic Bcl-2 inhibition lesions, transcriptional upregulation, ligand-dependent autocrine or paracrine mechanisms [Bean et al. 2007; Schmidt et al. 1997; Houldsworth et al. 1990].
Inherited and somatic mutations in MET have been found in papillary renal carcinoma tumor samples, providing strong direct evidence of the pathway??s oncogenic potential [Jeffers et al. 1997; Schmidt et al. 1997]. In addition, there is accumulating evidence that acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors and angiogenesis inhibitors can be due, in part, to increased activation of the c- MET pathway [Ebos et al. 2009; Engelman et al. 2007]. For example, amplification of MET leads to gefitinib resistance in lung cancer by mediating HER3-dependent jak stat activation of PI3 kinase and these tumors are sensitive to c-MET inhibitors [Bean et al. 2007; Engelman et al. 2007]. Approaches to inhibiting the c-MET axis in the clinic Several strategies have been developed to inhibit the c-MET signaling pathway in cancer, each focusing on one of the serial steps that regulate MET activation (Figure 1).
These strategies include selective c-MET kinase inhibitors such as tivantinib (ARQ 197), JNJ-38877605 and PF04217903 which have specific selectivity for c-MET receptor tyrosine kinases; nonselective c-MET kinase inhibitors such as PF02341066, cabozantinib (XL184), GSK1363089, MK- 2461, MP470 and MGCD265 which have broad activity against c-MET and other receptor tyrosine kinases; anti-c-MET monoclonal antibodies (MetMAb) are also selective, but bind to the receptor, leading to internalization and degradation as opposed to inhibiting tyrosine kinase activity; anti-HGF monoclonal antibodies (AMG102, SCH900105) bind to the STAT Signaling Pathway circulating ligand, HGF; and c-MET/HGF competitors (NK4). In this review, an overview of c-MET pathway inhibitors will be provided, supported by available phase II clinical trial data.

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