Acquired resistance is a major obstacle for conventional cancer chemotherapy, and also for some of the targeted therapies approved to date. Long‐term treatment using 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 phosphatidylinositol 3‐kinase inhibitors (PI3Kis), little is known about their acquired resistance, although some are undergoing clinical trials. To address this issue, we exposed 11 human cancer cell lines to ZSTK474, a PI3Ki we developed previously, for a period of more than 1 year in vitro. Consequently, we established ZSTK474‐resistant cells from four of the 11 cancer cell lines tested. The acquired resistance was not only to ZSTK474 but also to other PI3Kis. None of the PI3Ki‐resistant 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. Interestingly, targeted knockdown of IGF1R expression using specific siRNAs or inhibition of IGF1R using IGF1R‐TKIs reversed the acquired PI3Ki resistance. These results suggest that long‐term treatment with PI3Kis may cause acquired resistance, and targeting IGF1R is a promising strategy to overcome the resistance.
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.
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.
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
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