Dual inhibition of EGFR at protein and activity level via combinatorial blocking of PI4KIIα as anti-tumor strategy

Our previous studies indicate that phosphatidylinositol 4-kinase Ⅱα can promote the growth of multi-malignant tumors via HER-2/PI3K and MAPK pathways. However, the molecular mechanisms of this pathway and its potential for clinical application remain unknown. In this study, we found that PI4KⅡα could be an ideal combinatorial target for EGFR treatment via regulating EGFR degradation. Results showed that PI4KⅡα knockdown reduced EGFR protein level, and the expression of PI4KⅡα shows a strong correlation with EGFR in human breast cancer tissues (r=0.77, P < 0.01). PI4KⅡα knockdown greatly prolonged the effects and decreased the effective dosage of AG-1478, a specific inhibitor of EGFR. In addition, it significantly enhanced AG1478-induced inhibition of tumor cell survival and strengthened the effect of the EGFR-targeting anti-cancer drug Iressa in xenograft tumor models. Mechanistically, we found that PI4KⅡα suppression increased EGFR ligand-independent degradation. Quantitative proteomic analysis by stable isotope labeling with amino acids in cell culture (SILAC) and LC-MS/MS suggested that HSP90 mediated the effect of PI4KⅡα on EGFR. Furthermore, we found that combined inhibition of PI4KⅡα and EGFR suppressed both PI3K/AKT and MAPK/ERK pathways, and resulted in downregulation of multiple oncogenes like PRDX2, FASN, MTA2, ultimately leading to suppression of tumor growth. Therefore, we conclude that combined inhibition of PI4KⅡα and EGFR exerts a multiple anti-tumor effect. Dual inhibition of EGFR at protein and activity level via combinatorial blocking of PI4KⅡα presents a novel strategyto combat EGFR-dependent tumors.