MET kinase inhibitor SGX523 synergizes with epidermal growth factor receptor inhibitor erlotinib in a hepatocyte growth factor-dependent fashion to suppress carcinoma growth.
The hepatocyte growth factor (HGF)-MET pathway supports several hallmark cancer traits, and it is frequently activated in a broad spectrum of human cancers (http://www.vai.org/met/). With the development of many cancer drugs targeting this pathway, there is a need for relevant in vivo model systems for preclinical evaluation of drug efficacy. Here, we show that production of the human HGF ligand in transgenic severe combined immunodeficient mice (hHGF(tg)-SCID mice) enhances the growth of many MET-expressing human carcinoma xenografts, including those derived from lung, breast, kidney, colon, stomach, and pancreas. In this model, the MET-specific small-molecule kinase inhibitor SGX523 partially inhibits the HGF-dependent growth of lung, breast, and pancreatic tumors. However, much greater growth suppression is achieved by combinatorial inhibition with the epidermal growth factor receptor (EGFR) kinase inhibitor erlotinib. Together, these results validate the hHGF(tg)-SCID mouse model for in vivo determination of MET sensitivity to drug inhibition. Our findings also indicate that simultaneously targeting the MET and EGFR pathways can provide synergistic inhibitory effects for the treatment of cancers in which both pathways are activated.
Zhang
Yu-Wen
YW
Van Andel Research Institute, Grand Rapids, MI, USA. YuWen.Zhang@vai.org
Staal
Ben
B
Essenburg
Curt
C
Su
Yanli
Y
Kang
Liang
L
West
Rich
R
Kaufman
Dafna
D
Dekoning
Tom
T
Eagleson
Bryn
B
Buchanan
Sean G
SG
Vande Woude
George F
GF
D000818:Animals; D002277:Carcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects; D004357:Drug Synergism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000069347:Erlotinib Hydrochloride; D005260:Female; D017228:Hepatocyte Growth Factor / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008809:Mice, Inbred C3H; D016513:Mice, SCID; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors*; D011724:Pyridazines / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D017978:Receptors, Growth Factor / Q000037:antagonists & inhibitors*; D014230:Triazoles / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
C547925:6-(6-(1-methyl-1H-pyrazol-4-yl)-(1,2,4)triazolo(4,3-b)pyridazin-3-ylsulfanyl)quinoline; D047428:Protein Kinase Inhibitors; D011724:Pyridazines; D011799:Quinazolines; D017978:Receptors, Growth Factor; D014230:Triazoles; D017228:Hepatocyte Growth Factor; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met