Abstract 4450: Identification of IGF1R as a responsible factor and a therapeutic target for overcoming acquired and intrinsic resistance to PI3K inhibitors.

Abstract

The phosphatidylinositol 3-kinase (PI3K) pathway is frequently activated in human cancers. Therefore PI3K is thought to be a promising target for cancer therapy, and many compounds targeting PI3K have been developed and tested in clinical trials. Acquired resistance is a major obstacle for conventional cancer chemotherapy, and also for some of the targeted therapies approved to date. Long-term administration of protein tyrosine kinase inhibitors (TKIs), such as gefitinib and imatinib, gives rise to resistant cancer cells carrying a drug-resistant gatekeeper mutation in the kinase domain of the respective target genes, EGFR and BCR-ABL. As for the PI3K inhibitors (PI3Kis), little is known about their acquired resistance. To address this issue, we established four human cancer cell lines that exhibited resistance to ZSTK474, a PI3Ki we developed previously, after drug exposure for a period of more than 1-year in vitro. None of the PI3Ki-reistant cells, however, contained any mutation in the kinase domain of the PIK3CA gene. Instead, we found that insulin-like growth factor 1 receptor (IGF1R) was overexpressed in all four resistant cells. Furthermore, PI3Ki-naïve cancer cells expressing high levels of IGF1R also exhibited resistance to PI3Kis. Interestingly, IGF1R-TKIs strongly enhanced the efficacy of PI3Ki in these cells. Thus, we propose that IGF1R could serve as a biomarker to predict the inefficacy of PI3K inhibitors, and also could be a target for overcoming acquired and intrinsic resistance in IGF1R-overexpressing cancers. Citation Format: Shingo Dan, Sho Isoyama, Yumiko Nishimura, Naoki Nakamura, Gensei Kajiwara, Naomi Tamaki, Mutsumi Okamura, Takao Yamori. Identification of IGF1R as a responsible factor and a therapeutic target for overcoming acquired and intrinsic resistance to PI3K inhibitors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4450. doi:10.1158/1538-7445.AM2013-4450