Abstract 3235: The IGF1 inhibitor BMS-754807 synergizes with Lapatinib in colorectal cancer cell lines
Authors: Peters Kristi L. , Dicker David T. , Abdallah Kald , Dhar Arindam , Woolfson Adrian , El-Deiry Wafik S. 
Published: August 2012

Abstract
Colorectal cancer is the second leading cause of cancer deaths worldwide. Early screening has improved survival rates, but at the time of diagnosis, a significant percentage of patients have advanced disease. Despite improved chemotherapy regimens, the average rate of survival remains less than two years. Drugs that target the epidermal growth factor (EGF) pathway have proven to be beneficial in patients who retain a wild-type KRAS. However 40% of colorectal tumors have a mutated KRAS, and are resistant to EGF-based therapies. One new approach is to target pathways that regulate cancer cell metabolism. The insulin-like growth factor-1 (IGF1) pathway regulates cell growth and motility, activates anti-apoptotic pathways and increases the frequency of cancer stem cells (CSCs). We have previously shown that inhibition of IGF1 signaling with a monoclonal antibody that blocks the IGF1R receptor, inhibited metastasis. In the current study, we examined whether simultaneous inhibition of the IGF1 and EGF pathways would be sufficient to block AKT activation and induce cell death, and also whether the dual targeting of these pathways would increase the cytotoxicity of other anticancer therapies. We report here that the small molecule inhibitor BMS-754807, which blocks the IGF1 and insulin receptors with equal potency, effectively kills a panel of 8 human colorectal cancer cell lines as determined using cell viability assays. The IGF-1R/IR dual inhibitor was found to reduce the size of the cancer stem cell population in several cell lines when measured by side-population analysis. No additional cell death was observed when the IGF1 inhibitor was used in combination with 5-FU and Irinotecan, however, when BMS-754807 was combined with an EGF pathway inhibitor synergy in the induction of cell death was observed in a subset of colorectal cancer cell lines. This effect was seen with the EGFR small molecule inhibitor Lapatinib, but not with the monoclonal antibody Cetuximab. While both Lapatinib and Cetuximab inhibited ERK activation, AKT activation was only inhibited by combination therapy with BMS-754807 and Lapatinib. EGFR activation was, furthermore, inhibited by BMS-754807 alone indicating that there may be cross-talk between the two pathways. We have previously reported that Lapatinib has off target effects in colorectal cancer cell lines, which require higher doses of Lapatinib and induction of DR5 via the JNK pathway. We are currently investigating whether the observed synergy between Lapatinib and BMS-754807 involves off target effects of Lapatinib, although the synergy observed is at doses thought to specifically target the EGFR family. The synergy between BMS-754807 and Lapatinib was observed in cell lines that have mutant BRAF as well as in those with mutant KRAS. This drug combination may consequently provide a new potential treatment strategy for patients who do not derive benefit from current EGFR-based therapies.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3235. doi:1538-7445.AM2012-3235