Basal expression of insulin‐like growth factor 1 receptor determines intrinsic resistance of cancer cells to a phosphatidylinositol 3‐kinase inhibitor ZSTK474

Abstract

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.

Functional evolution of IGF2:IGF2R domain 11 binding generates novel structural interactions and a specific IGF2 antagonist

“…The synergistic effects with PI3 kinase inhibitors reported here are also in keeping with reports of the intrinsic resistance conferred by the IGF pathway following PI3 kinase inhibition (ZSTK474) in gastric carcinoma cell lines, suggesting that conditional effects acting directly on the intracellular signaling pathway may unmask such IGF1R/IR-A and IGF2 ligand dependency (54). Similar intracellular feedback mechanisms may extend to regulation of ligand bioavailability, given that EGFR pathway resistance may be conferred by reduced IGFBP levels, and resistance to IGF pathway inhibition may be improved by downstream MEK inhibition (55,56).…”

Antitumor profile of the PI3K inhibitor ZSTK474 in human sarcoma cell lines

“…In our previous study using the JFCR39 carcinoma cell line panel, gain of function mutations of the KRAS or BRAF genes and overexpression of IGF1R were found to be negative predictors whereas high expression of phosphorylated AKT was observed to be a positive predictor for ZSTK474 efficacy [ 40 ]; however, neither gain of function mutations of KRAS / NRAS / BRAF nor overexpression of IGFR/phosphorylated AKT displayed any significant correlation with ZSTK474 efficacy in the sarcoma panel assessed here. HT-1080, one of the less effective cell lines examined, harbored gain of function mutation of NRAS , suggesting that NRAS mutation could be involved ZSTK474 inefficacy; however, RD, another NRAS mutant cell line, responded to ZSTK474 at a moderate level.…”

Absence of renal enlargement in fructose-fed proximal-tubule-select insulin receptor (IR), insulin-like-growth factor receptor (IGF1R) double knockout mice

“…The IGF type 1 receptor (IGF1R, Igf1r) and IR are coupled to related, but not identical, signaling cascades in many cell types. IGF (both I and II) is associated primarily with mitogenic/growth pathways, and has been demonstrated to have a role in tumor biology (Isoyama et al 2015). In contrast, insulin's actions are primarily metabolic and include uptake of glucose into cells, as well as, down-regulation of glucose-production pathways, including gluconeogenesis in liver and likely renal PT (Siddle 2011).…”