Abstract 537: Is interrupting IGF1R signaling enough to overcome resistance to trastuzumab in HER2+ breast cancer models?.
Authors: Sun Yuliang , Dey Nandini , Hasmann Max , De Pradip , Leyland-Jones Brian 
Published: August 2014

Abstract
Background: Trastuzumab resistance hampers its well-known efficacy in controlling HER2+ breast cancer progression. IGF1R is associated with worse outcomes in the HER2+ subtype of breast cancer (Br Cancer Res Treat 2012 132:131). Indeed, there is in vitro evidence showing that increased signaling through IGF1R confers resistance to HER2-targeting agents. However, the involvement of IGF1R and its downstream signaling pathways in this mechanism have yet to be confirmed. Purpose: Since, IGF1R is involved in the progression of breast cancers and resistance to trastuzumab therapy, co-suppression of this pathway with IGF1R mAB plus trastuzumab (T) or T-DM1 may, therefore, be efficacious in T-resistant breast cancer models. Methods: Here, we investigated the preclinical efficacy of IGF1R mAB (R7072) alone or in combination with T or T-DM1 in BT474/HerR (T-resistant) and MCF7/HER2-18 (HER2 stably overexpressed) cell lines. The inhibition of IGF1R pathway effectors was evaluated by Western blotting. Tumor growth inhibition after treatment of R7072, T/T-DM1 or the combination was examined in cell-based xenograft models. Results: 1) Doses as low as 10 μg/ml, R7072 abrogated p- AKT (S473 and T308) within 1hr of treatment in both MC7/HER2-18 and MCF7 cells (parental), 2) R7072 transiently blocked phosphorylation of downstream effector of mTOR, P70S6K (in 1hr treatment) in MCF7/HER2-18 cells but completely blocked of phosphorylation of P70S6K in MCF7 cells in both time points, 3) IGF1-induced AKT activation was inhibited in both HER2 overexpressed MCF7 and parental cells, however, both T and T-DM1 failed to block AKT activation following IGF1 stimulation in both cell lines, 4) in both cell lines, treatment of R7072 resulted in upregulation of p-ERK at higher time points, 5) R7072 was unable to block PI3K and its downstream effectors in HER2+/T-resistant cells, 6) in vivo xenograft data show that the combination of R7072 and T/T-DM1 has strongly enhanced antitumor effects in both MCF7/HER2-18 and BT474/HerR cells, but as a single agent, R7072 failed to block tumor growth in HER2+/T-resistant cells, and 5) similarly this combination significantly blocked the expression Ki67 and CD31 in tumor tissues. Conclusion: Our data suggest that the combination of R7072 and anti-HER2 antibody (T or T-DM1) is highly effective in the HER2+/T-resistant model and that similar level of inhibition cannot be achieved by either monotherapy.
Citation Format: Yuliang Sun, Nandini Dey, Max Hasmann, Pradip De, Brian Leyland-Jones. Is interrupting IGF1R signaling enough to overcome resistance to trastuzumab in HER2+ breast cancer models?. [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 537. doi:10.1158/1538-7445.AM2013-537
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.