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 strategy to combat EGFR-dependent
tumors.