Hepatocyte growth factor/MET in cancer progression and biomarker discovery

Abstract

Signaling driven by hepatocyte growth factor (HGF) and MET receptor facilitates conspicuous biological responses such as epithelial cell migration, 3-D morphogenesis, and survival. The dynamic migration and promotion of cell survival induced by MET activation are bases for invasion-metastasis and resistance, respectively, against targeted drugs in cancers. Recent studies indicated that MET in tumor-derived exosomes facilitates metastatic niche formation and metastasis in malignant melanoma. In lung cancer, gene amplification-induced MET activation and ligand-dependent MET activation in an autocrine/paracrine manner are causes for resistance to epidermal growth factor receptor tyrosine kinase inhibitors and anaplastic lymphoma kinase inhibitors. Hepatocyte growth factor secreted in the tumor microenvironment contributes to the innate and acquired resistance to RAF inhibitors. Changes in serum/plasma HGF, soluble MET (sMET), and phospho-MET have been confirmed to be associated with disease progression, metastasis, therapy response, and survival. Higher serum/plasma HGF levels are associated with therapy resistance and/or metastasis, while lower HGF levels are associated with progression-free survival and overall survival after treatment with targeted drugs in lung cancer, gastric cancer, colon cancer, and malignant melanoma. Urinary sMET levels in patients with bladder cancer are higher than those in patients without bladder cancer and associated with disease progression. Some of the multi-kinase inhibitors that target MET have received regulatory approval, whereas none of the selective HGF-MET inhibitors have shown efficacy in phase III clinical trials. Validation of the HGF-MET pathway as a critical driver in cancer development/progression and utilization of appropriate biomarkers are key to development and approval of HGF-MET inhibitors for clinical use.

Keywords: HGF; MET; Biomarker; drug resistance; receptor tyrosine kinase.

Figure 1

Structures of MET (a), hepatocyte growth factor (HGF) (b), and the complex between the β‐chain of HGF and SEMA and plexin–semaphorin–integrin (PSI) domains of MET (c). In (a), tyrosine residues (Y1234, Y1235, Y1349, and Y1356) phosphorylated following HGF stimulation in the tyrosine kinase (TK) domain are shown in blue. In (c), positions of missense mutations found in cancer patients are indicated by red balls. The image of PDB ID 1SHY (Stamos J, Lazarus RA, Yao X, Kirchhofer D, Wiesmann C. Crystal structure of the HGF β‐chain in complex with the Sema domain of the Met receptor. EMBO J. 23: 2325, 2004) was created with PyMOL.

Figure 2

Outline of the mechanism for metastasis promoted by the hepatocyte growth factor (HGF)‐MET pathway and tumor‐derived exosomes in advanced metastatic melanoma. Peinado et al. showed that tumor‐derived exosomes from advanced metastatic melanoma contained high levels of MET, and the exosomes induced an increase in the phosphorylated/activated MET in bone marrow‐derived cells, thereby resulting in a mobilization of the bone marrow‐derived cells to the lungs and lymph nodes, where they initiated metastatic niche formation.28 Collectively, HGF facilitates local invasion, extravasation, and intravasation, and MET in exosomes facilitates angiogenesis and metastatic niche formation.

Figure 3

MET mutations found in cancer patients. (a) Positions of missense and deletion mutations in each domain of MET. The deletion mutations in extracellular immunoglobulin‐like fold–plexin–transcription factor (IPT) domains and the intracellular juxtamembrane (JM) domain are caused by exon skipping.43, 44, 45 (b) Crystal structures of MET tyrosine kinase (TK) domain and positions of missense activating mutations found in patients with papillary renal cell carcinoma. Amino acids changed by missense mutations are indicated by red balls. The autoinhibited form (left panel, PDB ID 2G15) and crizotinib (a dual inhibitor for anaplastic lymphoma kinase and MET) bound form (right panel, PDB ID 2WGJ) are shown. The structural change of the activation loop (A1221–K1248, colored red) occurs following Y1234/Y1235 phosphorylation and upregulates enzymatic activity. The images of PDB ID 2G15 (left) (Wang W, Marimuthu A, Tsai J, Kumar A, Krupka HI, Zhang C, Powell B, Suzuki Y, Nguyen H, Tabrizizad M, Luu C, West BL. Structural characterization of autoinhibited c‐Met kinase produced by coexpression in bacteria with phosphatase. Proc Natl Acad Sci USA. 103: 3563‐3568, 2006) and PDB ID 2WGJ (right) (Cui JJ, Tran‐Dubé M, Shen H, Nambu M, Kung PP, Pairish M, Jia L, Meng J, Funk L, Botrous I, McTigue M, Grodsky N, Ryan K, Padrique E, Alton G, Timofeevski S, Yamazaki S, Li Q, Zou H, Christensen J, Mroczkowski B, Bender S, Kania RS, Edwards MP. Structure based drug design of crizotinib (PF‐02341066), a potent and selective dual inhibitor of mesenchymal‐epithelial transition factor (c‐MET) kinase and anaplastic lymphoma kinase (ALK). J Med Chem. 54: 6342‐6363, 2011) were created with PyMOL.