title: Microenvironment-derived HGF overcomes genetically determined sensitivity to anti-MET drugs.
abstract: Cell-based drug screenings indicate that tumors displaying c-MET gene amplification are "addicted" to MET signaling and therefore are very sensitive to MET-targeted agents. However, these screenings were conducted in the absence of the MET ligand, hepatocyte growth factor (HGF), which is abundant in the tumor microenvironment. Sensitivity of six MET-addicted human tumor cells to three MET kinase inhibitors (JNJ-38877605, PHA-665752, crizotinib) and one antagonistic anti-MET antibody (DN30 Fab) was analyzed in the absence or presence of HGF, in a stroma-tumor coculture system, and by combining anti-MET drugs with an HGF neutralizing antibody (ficlatuzumab) in human HGF knock-in mice bearing c-MET-amplified tumors. In all models examined, HGF promoted resistance to MET-targeted agents, affecting both their potency and efficacy. HGF-induced resistance was due to restoration of physiologic GAB1-mediated PI3K activation that compensated for loss of aberrant HER3-dependent PI3K signaling. Ficlatuzumab restored sensitivity to MET-targeted agents in coculture systems and overcame resistance to JNJ-38877605, crizotinib, and DN30 Fab in human HGF knock-in mice. These data suggest that c-MET-amplified tumor cells-which normally exhibit ligand-independent, constitutive MET activation-become dependent on HGF for survival upon pharmacologic MET inhibition. Because HGF is frequently overexpressed in human cancer, this mechanism may represent a major cause of resistance to anti-MET therapies. The ability of ficlatuzumab to overcome HGF-mediated resistance generates proof of principle that vertical inhibition of both a tyrosine kinase receptor and its ligand can be therapeutically beneficial and opens new perspectives for the treatment of MET-dependent tumors.
authors.affiliation: Department of Oncology, University of Torino Medical School, Candiolo, Torino, Italy. Candiolo Cancer Institute - FPO, IRCCS, Candiolo, Torino, Italy. Clinical Pathology Specialty School, University of Torino, Torino, Italy.
authors.forename: Selma
authors.initials: S
authors.lastname: Pennacchietti
authors.affiliation: Department of Oncology, University of Torino Medical School, Candiolo, Torino, Italy. Candiolo Cancer Institute - FPO, IRCCS, Candiolo, Torino, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Cazzanti
authors.affiliation: Department of Oncology, University of Torino Medical School, Candiolo, Torino, Italy. Candiolo Cancer Institute - FPO, IRCCS, Candiolo, Torino, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Bertotti
authors.affiliation: AVEO Pharmaceuticals, Cambridge, Massachusetts.
authors.forename: William M
authors.initials: WM
authors.lastname: Rideout
authors.affiliation: AVEO Pharmaceuticals, Cambridge, Massachusetts.
authors.forename: May
authors.initials: M
authors.lastname: Han
authors.affiliation: AVEO Pharmaceuticals, Cambridge, Massachusetts.
authors.forename: Jeno
authors.initials: J
authors.lastname: Gyuris
authors.affiliation: Janssen Research & Development, Beerse, Belgium.
authors.forename: Timothy
authors.initials: T
authors.lastname: Perera
authors.affiliation: Department of Oncology, University of Torino Medical School, Candiolo, Torino, Italy. Candiolo Cancer Institute - FPO, IRCCS, Candiolo, Torino, Italy.
authors.forename: Paolo M
authors.initials: PM
authors.lastname: Comoglio
authors.affiliation: Department of Oncology, University of Torino Medical School, Candiolo, Torino, Italy. Candiolo Cancer Institute - FPO, IRCCS, Candiolo, Torino, Italy.
authors.forename: Livio
authors.initials: L
authors.lastname: Trusolino
authors.affiliation: Department of Oncology, University of Torino Medical School, Candiolo, Torino, Italy. Candiolo Cancer Institute - FPO, IRCCS, Candiolo, Torino, Italy. paolo.michieli@ircc.it.
authors.forename: Paolo
authors.initials: P
authors.lastname: Michieli
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017228:Hepatocyte Growth Factor / Q000494:pharmacology*; D051379:Mice; D016513:Mice, SCID; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000502:physiology; D020893:Receptor, ErbB-3 / Q000502:physiology; D015398:Signal Transduction; D059016:Tumor Microenvironment
chemical_list: D000911:Antibodies, Monoclonal; D017228:Hepatocyte Growth Factor; C583360:ficlatuzumab; D019869:Phosphatidylinositol 3-Kinases; D019859:Proto-Oncogene Proteins c-met; D020893:Receptor, ErbB-3