American Association for Cancer Research
00085472can140761-sup-128494_2_supp_2620374_nyljpl.pptx (262.5 kB)

Supplementary Figure 2 from Microenvironment-Derived HGF Overcomes Genetically Determined Sensitivity to Anti-MET Drugs

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posted on 2023-03-30, 22:49 authored by Selma Pennacchietti, Manuela Cazzanti, Andrea Bertotti, William M. Rideout, May Han, Jeno Gyuris, Timothy Perera, Paolo M. Comoglio, Livio Trusolino, Paolo Michieli

Supplementary Fig. 2. HGF sustains HER3-independent PI3K signaling in c-MET-amplified cells exposed to MET tyrosine kinase inhibitors.



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. ©2014 AACR.