American Association for Cancer Research
00085472can140761-sup-128494_2_supp_2620375_nfljpl.pptx (278.45 kB)

Supplementary Figure 3 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. 3. HGF restores physiological, GAB-1-mediated MET signaling in DN30 Fab-treated MET-addicted cells.



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.