Single-agent and combination therapeutic strategies to inhibit hepatocyte growth factor/MET signaling in cancer.
Receptor tyrosine kinases are often aberrantly activated in human malignancies and contribute to cancer development and progression. Specific receptor tyrosine kinase inhibitors have been shown to be clinically effective therapies in subsets of cancer patients with either hematologic or solid tumors. Activation of the hepatocyte growth factor (HGF)/MET signaling pathway has been found to play a critical role in oncogenesis, cancer metastasis, and drug resistance. These observations have led to the development of agents that can effectively inhibit HGF/MET signaling through direct inhibition of the receptor (anti-MET antibodies), through inactivation of its ligand HGF (AMG102, L2G7), by interfering with HGF binding to MET (NK4), or by inhibiting MET kinase activity (PHA-665752 and SU11274). Moreover, the combination of anti-MET therapeutic agents with either signal transduction inhibitors (ERBB family or mTOR inhibitors) or with cytotoxic chemotherapy has been evaluated in preclinical models. These studies provide insight into the rational development of combination therapeutic strategies that can be evaluated in clinical trials. This review will discuss different strategies of MET inhibition with a specific focus on combination therapeutic approaches.
Toschi
Luca
L
Lowe Center for Thoracic Oncology and Department of Medical Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115, USA.
Jänne
Pasi A
PA
D000970:Antineoplastic Agents / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D017228:Hepatocyte Growth Factor / Q000037:antagonists & inhibitors*; D006801:Humans; D008954:Models, Biological; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding; D015398:Signal Transduction
D000970:Antineoplastic Agents; D017228:Hepatocyte Growth Factor