Abstract 1813: Insulin-like growth factor receptor and sphingosine kinase co-expression has prognostic and therapeutic potential in breast cancer

Abstract

Abstract The search for reliable prognostic markers of breast cancer disease outcome is ongoing. The insulin-like growth factor receptor (IGF1R) and sphingosine kinase (SphK1) signaling pathways are known to contribute to breast oncogenesis and are therapeutic targets [1, 2]. Since IGF-I signaling activates SphK1 [3] we hypothesized that high IGF1R and SphK1 co-expression may be clinically relevant, and potential dual therapeutic targets in breast cancer. Kaplan-Meier analysis was performed to determine the prognostic significance of IGF1R and SphK1 high co-expression on disease free survival (DFS) and overall survival (OS) probability in breast cancer (http://glados.ucd.ie/BreastMark/). Cell viability studies and clonogenic assays were undertaken using the luminal, estrogen receptor (ER)-positive MCF7 and T47D and the basal-like, ER-negative HCC-1806 and HCC70 breast cancer cells to test the effectiveness of the dual IGF1R and insulin receptor inhibitor (OSI-906; 0.1 - 10 μM) and the SphK1 inhibitor (SKI-II; 1 - 20 μM) as single and combined agents. Statistical analysis was completed using a one-way ANOVA (p<0.05), repeated measures (p<0.05) and calculation of drug synergism by a combination index (CI) <1 (CommSyn). Immunoblot analysis was used to show effective drug target inhibition of IGF1R and SphK1. IGF1R and SphK1 high co-expression was associated with decreased DFS (HR; 2.184 (1.007 - 4.735, p = 0.042; total 270 patients) and OS (HR; 2.433 (1.136 - 5.214, p = 0.018; total 170 patients) in ER-positive, luminal A, lymph-node positive breast cancers compared to no significance using single-gene analysis. A reduction in OS in basal, ER-negative, lymph node negative breast cancers was associated with high IGF1R and SphK1 co-expression (HR; 5.687 (1.534 - 21.084, p = 0.003; total 55 patients), compared to high IGF1R expression alone (HR; 4.103 (1.34 - 12.57, p = 0.007; total 55 patients). In all four cell-lines 4 μM SKI-II acted synergistically with OSI over the range 0.1 - 6.4 μM (CI<1), and significantly increased sensitivity towards OSI (p<0.05). p-IGF1R and SphK1 protein levels were both reduced by SKI-II and OSI-906 in the HCC-1806 and HCC70 cell-lines, revealing a reciprocal regulation of signaling and effective drug treatment. Based on the limited clinical success of the IGF1R mono-therapies better predictive markers of IGF1R activity are now required for the development of more effective IGF1R-directed combination therapies. Collectively, these studies have identified: i) IGF1R and SphK1 expression are potentially co-dependent and have prognostic significance and ii) a novel IGF1R targeted combination therapy that may be of clinical benefit to specific molecular subtypes of breast cancer. 1. Martin, J.L., et al., Mol Cancer Ther, 2014. 13(2): p. 316-28. 2. Beckwith, H. and D. Yee., Endocr Pract, 2014. 20(11): p. 1214-21. 3. Granata, R., et al., J Thromb Haemost, 2007. 5(4): p. 835-45. Citation Format: Aleksandra M. Ochnik, Robert C. Baxter. Insulin-like growth factor receptor and sphingosine kinase co-expression has prognostic and therapeutic potential in breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1813.