These data thus suggest that, in some under cases, co targeting Inhibitors,Modulators,Libraries of both these molecules could be of clinical importance. Several experimental evidences suggest the existence of biochemical and functional interplays between the mem bers of the HER family and MET. Moreover, recent stud ies have shown that resistance to Gefitinib can be due to MET amplification. In this case, MET overexpression and constitutive activation leads to HER3 trans phospho rylation and activation of HER3 dependent survival path ways. In these cells, co inhibition of MET and EGFR reverted resistance to Gefitinib. Since MET plays a role in mediating resistance to EGFR inhibition, we wondered if also the reversal was true.

Some works have shown that, in vitro, activation of HER family members can lead to MET phosphorylation, but the role of this interplay has never been evaluated Inhibitors,Modulators,Libraries in vivo and in the contest of cells resistant to MET inhibitors. As works conducted on other RTKs highlighted the ability of laboratory models to identify clinically relevant mechanisms of drug resistance, the aim Inhibitors,Modulators,Libraries of our work was to try to evaluate, in vitro and in preclinical models, the possible role of HER family receptors in mediating pri mary resistance to MET inhibition. Inhibitors,Modulators,Libraries We took advantage of gastric MET addicted tumor cell lines that stop proliferating upon treatment with specific MET inhibitors. We found that activation of HER family members in MET addicted cells, after MET inactivation, is able to increase cell viability in vitro, and to recover tumorigenicity in vivo. This observation is important if translated into a clinical context.

In fact, gastric tumors that display MET gene amplification are potentially addicted to MET expression and can be con sidered ideal targets for anti MET therapies. however, aberrant activation of HER family members has also been shown to be concomitant Inhibitors,Modulators,Libraries in these tumors. This means that the effect of MET inhibition could potentially be neutralized or attenuated by the parallel activation of receptors of the HER family. This implies that combinato rial inhibition of both MET and HER could likely improve the therapeutic effect. It is critical MEK162 msds to underline that not all the growth factor activated pathways can compensate for the lack of signal due to MET inhibition, as shown by data reported in this paper. Differently from previous observations in HER addicted cells, the biological effects due to HER members activation was not due to their abil ity to trans phosphorylate MET. In fact, the resistance was present not only in cells in which MET was inhibited by the specific small molecule, but also in cells in which the receptor was no longer present and thus not avail able for trans phosphorylation due to shRNA mediated silencing.