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

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 PKCbeta 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 PKCbeta and MET, utilizing tissue microarrays under an IRB-approved protocol. Expression of PKCbeta and MET was evaluated in cell lines by immunoblotting. Treatment with SU1174 against MET and enzastaurin against PKCbeta was performed in H1993 and H358 cell lines, and cell proliferation and downstream signaling (phosphorylation of MET, AKT, FAK, and GSK3beta) 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 PKCbeta showed no correlation (p=0.204). MET and PKCbeta 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 PKCbeta 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 GSK3beta were strongly inhibited with both agents in combination. CONCLUSIONS: Concomitant inhibition of MET and PKCbeta significantly increased cytotoxicity in vitro against NSCLC, disrupting important downstream signaling pathways. Further evaluation in animal models is warranted.

Pleurectomy and decortication.

Pleurectomy and decortication (P/D) improve survival and quality of life in selected patients with malignant pleural mesothelioma. The operative procedure was not standardized until recently. The goal of the operation is to perform a macroscopic complete resection of the tumor. This often involves resection of the parietal and visceral pleura and invariably a partial or complete resection and prosthetic reconstruction of ipsilateral hemidiaphragm. We describe our operative planning and technique as well as outcomes of P/D reported in current literature.