Drug resistance often critically limits the efficacy of molecular targeted drugs. Although pharmacological inhibition of
phosphatidylinositol 3-kinase (PI3K) is an attractive therapeutic strategy for
cancer therapy, molecular determinants for efficacy of PI3K inhibitors (PI3Kis) remain unclear. We previously identified that overexpression of
insulin-like growth factor 1 receptor (IGF1R) contributed to the development of drug resistance after long-term exposure to PI3Kis. In this study, we examined the involvement of basal IGF1R expression in intrinsic resistance of
drug-naïve
cancer cells to PI3Kis and whether inhibition of IGF1R overcomes the resistance. We found that
cancer cells highly expressing IGF1R showed resistance to dephosphorylation of Akt and subsequent antitumor effect by
ZSTK474 treatment. Knockdown of IGF1R by siRNAs facilitated the dephosphorylation and enhanced the
drug efficacy. These cells expressed
tyrosine-phosphorylated
insulin receptor substrate 1 at high levels, which was dependent on basal IGF1R expression. In these cells, the efficacy of
ZSTK474 in vitro and in vivo was improved by its combination with the IGF1R inhibitor
OSI-906. Finally, we found a significant correlation between the basal expression level of IGF1R and the inefficacy of
ZSTK474 in an in vivo human
cancer panel, as well as in vitro. These results suggest that basal IGF1R expression affects intrinsic resistance of
cancer cells to
ZSTK474, and IGF1R is a promising target to improve the therapeutic efficacy. The current results provide evidence of combination
therapy of PI3Kis with IGF1R inhibitors for treating IGF1R-positive human
cancers.