Abstract 3998: The IGF1 receptor/insulin receptor dual kinase inhibitor BMS-754807 targets the cancer stem cell population in addition to its synergism with Lapatinib in colorectal cancer.
Authors: Peters Kristi L. , Dicker David T. , Woolfson Adrian , El-Deiry Wafik S. 
Published: August 2014

Colon cancer is the second leading cause of cancer mortalities each year. Current treatment options include drugs that target the epidermal growth factor (EGF) pathway. However, the use of these drugs is limited to individuals that are wild type for KRAS. New therapies are needed for patients who develop resistance to EGF-based therapies, as well as for the 40% of patients whose tumors have mutated KRAS. Our approach has been to target pathways that regulate cancer cell metabolism. The insulin and insulin-like growth factor-1 (IGF1) pathways regulate glucose metabolism, cell growth, cell motility and anti-apoptotic pathways. In colon cancer, IGF1 and insulin enhance tumor growth, promote metastasis and increase the cancer stem cell (CSC) population. In order to target the insulin and IGF-1 pathways simultaneously, we utilized the small molecule, dual kinase inhibitor BMS-754807 which inhibits the Insulin receptor (IR) and IGF1 receptor (IGF1R) with equal potency. We previously reported that the drug effectively reduced cell viability in a panel of eight colon cancer cell lines. In combination when combined with Lapatinib, an EGFR/HER2 small molecule dual kinase inhibitor, the drug showed synergistic effects on viability in a subset of cell lines. In order to determine the mechanism of the observed synergy, we examined whether EGFR and IGF1R were interacting directly as has been observed in breast cancer. Co-immunoprecipitation experiments in colorectal cancer cells, did not demonstrate an interaction between the EGFR and IGF1R. Examination of the signaling pathways in our panel of cell lines has determined that the regulation of ERK appears to be a critical determinant in sensitivity to the combination therapy. In both of the sensitive lines, AKT was strongly activated by IGF1, while ERK was strongly activated by EGF, but less substantially by IGF1. However in the cell lines that were insensitive to the BMS-754807/Lapatinib combination, substantial activation of ERK was observed in the absence of either EGF or IGF1. Therefore constitutive ERK activation in the absence of EGF signaling may be the determinant for sensitivity to the combined therapy. Finally, we examined the efficacy of BMS-754807 in the targeting colon cancer stem cells. In our panel of eight cell lines, BMS-754807 strongly inhibited colonsphere formation from the CSC population in three cell lines, and showed moderate inhibition in four of the five remaining lines. Of interest is the fact that the cells that were most sensitive to BMS-754807 in sphere formation were the most resistant in viability assays, and did not synergize with Lapatinib. These results are encouraging as we continue to develop strategies that specifically target the cancer stem cell, and indicate that BMS-754807 has multiple potential mechanisms of action in colon cancer.

Citation Format: Kristi L. Peters, David T. Dicker, Adrian Woolfson, Wafik S. El-Deiry. The IGF1 receptor/insulin receptor dual kinase inhibitor BMS-754807 targets the cancer stem cell population in addition to its synergism with Lapatinib in colorectal cancer. [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 3998. doi:10.1158/1538-7445.AM2013-3998