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.


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.
Faoro
Leonardo
L
Section of Hematology/Oncology, Department of Medicine, University of Chicago Pritzker School of Medicine, and University of Chicago Cancer Research Center, Chicago, IL 60637, USA.
Cervantes
Gustavo M
GM
Ferguson
Benjamin D
BD
Seiwert
Tanguy Y
TY
Yala
Soheil
S
Vigneswaran
Wicki T
WT
Westerhoff
Maria
M
Tretiakova
Maria S
MS
Ferguson
Mark K
MK
Moura
Glaci L
GL
Husain
Aliya N
AN
Vokes
Everett E
EE
Salgia
Ravi
R