MET/PKCβ expression correlate with metastasis and inhibition is synergistic in lung cancer

Abstract

Background: Treatment of non-small cell lung cancer (NSCLC) remains a difficult task in oncology. Targeted inhibition of oncogenic proteins is promising. In this study, we evaluate the expression of MET and PKC and in vitro effects of their inhibition using SU11274 and enzastaurin (LY317615.HCl) respectively. Materials and Methods: Patient samples were analyzed by immunohistochemistry for expression of PKC and MET, utilizing tissue microarrays under an IRB-approved protocol. Expression of PKC and MET was evaluated in cell lines by immunoblotting. Treatment with SU1174 against MET and enzastaurin against PKC was performed in H1993 and H358 cell lines, and cell proliferation and downstream signaling (phosphorylation of MET, AKT, FAK, and GSK3) were evaluated by immunoblotting. Statistical analysis was performed using SPSS 16.0. Results: Expression of MET positively correlated with lymph node metastases (p=.0004), whereas PKC showed no correlation (p=0.204). MET and PKC expression were also strongly correlated (p < 0.001). Expression of MET was observed in 5/8 cell lines (H358, H1703, A549, H1993, H2170; absent from H522, H661, or SW1573), whereas PKC expression was observed in 8/8 cell lines. Cell proliferation was significantly impaired by treatment with SU11274 and enzastaurin, and their effects were synergistic in combination (CI=0.32 and 0.09). Phosphorylation of MET, FAK, AKT, and GSK3 were strongly inhibited with both agents in combination. Conclusions: Concomitant inhibition of MET and PKC significantly increased cytotoxicity in vitro against NSCLC, disrupting important downstream signaling pathways. Further evaluation in animal models is warranted. © 2009 Faoro.