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. Cancer Res; 74(22); 6598-609. Ó2014 AACR.

Glesatinib Exhibits Antitumor Activity in Lung Cancer Models and Patients Harboring MET Exon 14 Mutations and Overcomes Mutation-mediated Resistance to Type I MET Inhibitors in Nonclinical Models

“…Capmatinib is also predicted to bind to the autoinhibited inactive conformation of MET as a type Ib inhibitor with interactions that involve pi-stacking with Y1230, but independently of G1163. In contrast, glesatinib exhibits a structure like type II inhibitors in the literature (30)(31)(32) and extends linearly toward the aC helix and hydrophobic back DFG-out pocket with a predicted primary binding mode as a type II inhibitor in catalytically inactive state. Glesatinib also appears capable of adopting a secondary binding mode to a DFG-in catalytically active state, extending back into a hydrophobic I1145 pocket between the aC helix and catalytic K1110.…”

The Therapeutic Potential of Targeting the HGF/cMET Axis in Ovarian Cancer

“…However, transcriptional upregulation has been observed resulting from Stat-3 and c-Src expression [60], and the co-expression of HGF and cMET in tumour cells can drive autocrine activation, as well as increased transcription for both genes. A number of studies have identified that HGF expression and autocrine cMET activation decreases sensitivity to cMET inhibitors, and stromal HGF levels have been linked to clinical responses in patients treated with the anti-HGF agent, ficlatuzumab [61][62][63], demonstrating the importance of the use of biomarkers in predicting clinical responses.…”

Targeting MET in Cancer: Obstacles and Potentials

“…MET-amplified tumor cells normally exhibit ligand-independent, constitutive MET activation [36]. Thus, in cancers driven by MET amplification/overexpression or activating mutations, MET activation and downstream signaling is unlikely to be fully blocked by drugs solely targeting HGF-MET binding.…”

“…Thus, in cancers driven by MET amplification/overexpression or activating mutations, MET activation and downstream signaling is unlikely to be fully blocked by drugs solely targeting HGF-MET binding. Furthermore, it was recently shown that microenvironmentderived HGF can overcome sensitivity to anti-MET drugs [36]. Similarly, HGF mAb such as rilotumumab alone may not be able to sufficiently attenuate MET signaling in HGF-independent tumors to deliver clinical benefit.…”

“…Recently, HGF-neutralizing antibody ficlatuzumab was shown to sensitize MET-amplified tumors to MET-targeted agents in animal model, providing proof of concept that combined inhibition of MET and HGF may represent a potentially successful strategy [36].…”