Abstract B226: Preclinical antitumor efficacy of the combination of the IGF-1R/IR dual kinase inhibitor OSI-906 with the MEK inhibitor selumetinib against colorectal cancer cell line and human tumor-derived xenografts.
Authors: Newton Timothy P. , Pitts Todd M. , Flanigan Sara A. , McManus Martine C. , Spreafico Anna , Arcaroli John , Eckhardt S. Gail , Leong Stephen 
Published: June 2012

Abstract
Background: OSI-906 is an orally bioavailable, selective dual kinase inhibitor of both insulin-like growth factor-1 receptor (IGF-1R) and insulin receptor (IR). Increased IGFR-1R and IR signaling has been associated with risk of several solid tumors including colon cancer. Previously, we tested the anti-proliferative effects of OSI-906 against a panel of 27 colorectal cancer (CRC) cell lines. Gene set enrichment analysis from the four most sensitive and five resistant cell lines revealed the MAPK pathway to be among the top 25 pathways up-regulated in resistant cell lines. Thus we explored the combination in vitro, and demonstrated that OSI-906 in combination with the MEK inhibitor, U0126, resulted in synergistic anti-proliferative effects, accompanied by down-regulation of pro-survival pathways and apoptosis. In the present study, we tested OSI-906 in combination with the MEK inhibitor selumetinib (AZD6244; ARRY-142866) in CRC models in vivo to confirm observations in vitro, and to provide additional support for this rational combination as a potential therapeutic strategy for patients with CRC.
Methods: Five to six week-old female nude mice were used for all animal studies. Two CRC cell lines (HCT15 and SW480) and one primary human CRC explant (CUCRC006) were used for the in vivo studies. All three models were resistant to both compounds as monotherapies. All mice were dosed daily (OSI-906) or twice daily (selumetinib) by oral gavage. Tumors were measured three times per week and tumor growth inhibition (TGI) was determined. Activation of downstream effectors and effectors of apoptosis was assessed by both immunoblotting and IHC.
Results: In the HCT15 model (resistant to both OSI-906 and selumetinib), synergistic/super-additive antitumor effects were observed in the combination group when compared to each single agent (TGI = 81%, 38%, and 37% for combination, OSI-906, and selumetinib, respectively), all of which was statistically significant (OSI-906 vs combo, p=0.015 and selumetinib vs combo, p=0.023). In the SW480 model, although combination treatment did show a benefit it was not statistically significant. (combo, 70%, OSI-906, 48%, and selumetinib, 32% TGI). In the human CRC explant CUCRC006, similar results to the HCT15 xenograft were observed. Combination treatment resulted in a lower TGI than either selumetinib or OSI-906 single agent treatment (64% vs 28% or 4.8% respectively). Corresponding with our in vitro results, analysis of tumor samples from the HCT15 or CUCRC006 models demonstrated down-regulation of pro-survival, anti-apoptotic, and growth pathways in the combination groups when compared to each single agent.
Conclusions: These data demonstrate that the combination of OSI-906 and selumetinib exhibits synergistic/super-additive effects against several CRC models in vivo. Further evaluation is ongoing to determine whether particular molecular subsets of CRC may be more responsive, since this rational strategy is one that should pursued further in a clinical setting.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B226.