Abstract 3606: Increase of MET gene copy number confers resistance to a monovalent MET antibody and establishes drug dependence

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA The tyrosine kinase receptor encoded by the MET oncogene is one of the most frequently altered oncogenes in human cancer. The relevant role played by the MET oncogene in cancer progression led to the development of specific inhibitors targeting MET, some of which are now in advanced phases of clinical trials. Previous experience has shown that the main limit to the efficacy of most targeted treatments is the advent of resistance. Mechanisms underlying resistance to MET-specific small tyrosine kinase inhibitors (TKIs) have been already described, while nothing is known about resistance to MET monoclonal antibodies, nor about bypassing resistance to chemical TKIs by antibodies or vice-versa. A monovalent form of an anti-MET monoclonal antibody (MV-DN30) was previously generated to target MET by promoting receptor “shedding”, inactivation and by inhibiting the MET-mediated invasive growth program both in vitro and in vivo cancer models. In our study EBC1 lung cancer cells that are MET-addicted as a consequence of gene amplification and thus sensitive to MET inhibitors, including the MV-DN30 were used as cell model. Upon prolonged treatment of these cells with the MV-DN30 we generated EBC1 cells resistant to this antibody and found that resistance was due to a further increase of MET gene copy number and a dramatic over-expression of the MET receptor. Such an excess of expression saturated the ‘shedding’ activity of MV-DN30, and prevented both the efficient down-regulation of the MET receptor from the surface and the inhibition of the ensuing constitutive activation. Notably, antibody-resistant cells became ‘drug-dependent’, since the removal of MV-DN30 led them to death due to an excess of MET signal and a concomitant p38MAPK activation. Moreover, antibody-resistant cells remained MET-’addicted’ and were still sensitive to MET TKIs. Finally, cells made resistant to MET specific TKIs were still sensitive to treatment with the antibody MV-DN30. These findings suggest that a discontinuous or combined treatment by antibodies and chemical kinase inhibitors may increase the clinical response and bypass resistance to anti-MET targeted therapies. Citation Format: Valentina Martin, Simona Corso, Paolo Maria Comoglio, Silvia Giordano. Increase of MET gene copy number confers resistance to a monovalent MET antibody and establishes drug dependence. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3606. doi:10.1158/1538-7445.AM2015-3606