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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.
AuthorsSho Isoyama, Gensei Kajiwara, Naomi Tamaki, Mutsumi Okamura, Hisashi Yoshimi, Naoki Nakamura, Kento Kawamura, Yumiko Nishimura, Nachi Namatame, Takao Yamori, Shingo Dan
JournalCancer science (Cancer Sci) Vol. 106 Issue 2 Pg. 171-8 (Feb 2015) ISSN: 1349-7006 [Electronic] England
PMID25483727 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Copyright© 2014 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.
Chemical References
  • Antineoplastic Agents
  • Phosphoinositide-3 Kinase Inhibitors
  • Triazines
  • ZSTK474
  • Receptor, IGF Type 1
  • Proto-Oncogene Proteins c-akt
Topics
  • Animals
  • Antineoplastic Agents (pharmacology)
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm (genetics)
  • Female
  • Heterografts
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Phosphatidylinositol 3-Kinases (metabolism)
  • Phosphoinositide-3 Kinase Inhibitors
  • Phosphorylation (genetics)
  • Proto-Oncogene Proteins c-akt (genetics)
  • Receptor, IGF Type 1 (genetics)
  • Triazines (pharmacology)

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