Abstract C92: MET amplification and overexpression sustain resistance and drive drug dependency to the DN30Fab antibody in MET-addicted cells.

The establishment of the oncogenic role of the tyrosine kinase receptor for hepatocyte growth factor, encoded by the MET gene, led to the development of several specific inhibitors, many of which are currently in clinical trials. Clinical experience has shown that the main limit to the efficacy of targeted treatments is represented by resistance. Although the mechanisms underlying resistance to MET-specific Tyrosine Kinase Inhibitors (TKIs) have been already described, nothing is known, up to now, about the emergence of resistance to treatment with MET monoclonal antibodies (mAbs). To predict the mechanisms of acquired resistance, we generated resistant cells by treating a MET-addicted lung cancer cell line (EBC1) with increasing concentrations of the monovalent form of the DN30mAb (DN30Fab), previously developed as a therapeutic tool to block MET activation. The molecular analyses revealed that resistant cells underwent MET amplification and reached such a level of MET overexpression that DN30Fab was no longer able to efficiently downregulate MET and to abrogate its constitutive activation. However, resistant cells remained MET-addicted as they were still sensitive to MET TKIs. Interestingly, resistant cells acquired drug dependence, since removal of DN30Fab led them to death due to excess of signal. Finally, we also show that cells with acquired resistance to MET TKIs are still sensitive to treatment with DN30Fab and that the two drugs have a synergistic effect on tumor cells. Our findings might have important clinical meaning, since they indicate a combined therapy (mAb plus TKI) and a discontinuous treatment as possible strategies to bypass resistance to anti-MET antibodies. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C92. Citation Format: Valentina Martin, Simona Corso, Fiorella Petronzelli, Rita De Santis, Paolo M. Comoglio, Silvia Giordano. MET amplification and overexpression sustain resistance and drive drug dependency to the DN30Fab antibody in MET-addicted cells. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C92.