Abstract C96: Development of combination therapy with an IGF1R inhibitor and a PI3K inhibitor ZSTK474 in cancer cells exhibiting the intrinsic resistance to PI3K inhibitors.
Authors: Isoyama Sho , Kajiwara Gensei , Tamaki Naomi , Yoshimi Hisashi , Nakamura Naoki , Okamura Mutsumi , Nishimura Yumiko , Yamori Takao , Dan Shingo 
Published: August 2014

Abstract
Background: Tumor cells can vary markedly in their response to anti-cancer drugs. Therefore predicting sensitivity or resistance of tumor cells to the drug and developing therapeutic strategies for overcoming the resistance is required to realize personalized medicine for cancer treatment. Although multiple drugs targeting phosphatidylinositol 3-kinase (PI3K) including ZSTK474 are undergoing clinical trials, little is known about the resistance. We previously reported that overexpression of insulin-like growth factor 1 receptor (IGF1R) contributed to acquired resistance to PI3K inhibitors (PI3Kis). In this study, we examined whether IGF1R contributes to intrinsic resistance to PI3Kis and whether combination of IGF1R tyrosine kinase inhibitor (IGF1R-TKI) and PI3Ki is an effective strategy for cancer cells exhibiting the intrinsic resistance to PI3Kis.
Materials and Methods: Correlation analyses between the expression level of IGF1R with the efficacy of PI3Ki across an in vitro panel of 39 human cancer cell lines (termed JFCR39) and a panel of 24 human tumor xenografts implanted in nude mice (termed JFCR24 xenografts) were performed. Specific siRNAs against IGF1R were used to examine the functional involvement of IGF1R in intrinsic resistance. Combination effect of ZSTK474 and an IGF1R-TKI OSI-906 was examined in vitro using isobologram analysis and in vivo using human tumor xenografts implanted in nude mice.
Results: Correlation analysis revealed that PI3Ki-naïve cancer cells expressing high levels of IGF1R exhibited resistance to ZSTK474 in vitro and in vivo. Targeted knockdown of IGF1R expression using specific siRNAs enhanced the efficacy of ZSTK474 in intrinsic resistant cell lines overexpressing IGF1R. In these cell lines, higher concentration of ZSTK474 was needed to dephosphorylate Akt compared to IGF1R-negative cell lines, and specific knockdown of IGF1R made it easier to dephosphorylate Akt after ZSTK474 treatment. Finally, we found a synergistic therapeutic effect of ZSTK474 in combination with OSI-906 in vivo, as well as in vitro.
Conclusion: PI3Ki-naïve cancer cells overexpressing IGF1R exhibited resistance to ZSTK474, but combination of ZSTK474 with an IGF1R-TKI exerted a remarkable therapeutic response in such cancer cells. We hope that our findings would contribute to personalized medicine using PI3Kis in future clinical application.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C96.
Citation Format: Sho Isoyama, Gensei Kajiwara, Naomi Tamaki, Hisashi Yoshimi, Naoki Nakamura, Mutsumi Okamura, Yumiko Nishimura, Takao Yamori, Shingo Dan. Development of combination therapy with an IGF1R inhibitor and a PI3K inhibitor ZSTK474 in cancer cells exhibiting the intrinsic resistance to PI3K inhibitors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C96.