Abstract 4261: Targeting HER3 and PI3K in head and neck squamous cancer cells.
Authors: Qing Sheng, HuiQin Wang, Rita Das, Yan Chen, Jinsheng Liang, Alex Cao, Carl Uli Bialucha, Seth Ettenberg, Alan Huang
Journal: Cancer Research (2013)

Abstract Background: Head and neck squamous cell carcinoma (HNSCC) is the fifth most common cancer worldwide, with more than 40,000 new cases developing annually in the US alone. 80-90% of HNSCC cases display elevated EGFR expression. Cetuximab an anti-EGFR monoclonal is an approved treatment of HNSCC. However, patient response to cetuximab is variable. Activation of the HER2/3 and/or the down stream PI3K pathway is a potential mechanism leading to cetuximab resistance in HNSCC. LJM716 is a fully human IgG1 ati-HER3 monoclonal antibody. BYL719 is a PI3Ka-selective small molecule inhibitor. Here, we profiled a panel of HNSCC cell lines for 1) the activation status of the EGFR/HER2/3/PI3K pathway; 2) their response to LJM716 and/or to BYL719 in combination with cetuximab. Methods: In this study, we evaluated LJM716 or BYL719 anti-tumor activity either alone, combined, or their respective combination with cetuximab in head and neck squamous cell cancer. LJM716, cetuximab and BYL719 single agent as well as combination activity of LJM716/cetuximab or LJM716/BYL719 were assessed in 33 head and neck cell lines using the CellTiter-Glo® Luminescent Cell Viability Assay. Single agent and combination anti-tumor activities of LJM716 were also tested in selected xenograft mouse models. To explore predictive markers for LJM716 and BYL719, baseline EGFR/HER2/3 and PI3K activation status was further analyzed. NRG1 level was assessed based on Affymetrix U133 plus2 genechip array. Results: Both BYL719 and LJM716 displayed anti-tumor activity in HNSCC cell lines in vitro, with BYL719 superior in most of the lines tested. There was minimum combination benefit observed with the combination of LJM716 and BYL719. Both reagents further enhanced cetuximab activity and expanded the number of cell lines sensitive to cetuximab. Anti-tumor activity was also observed with LJM716 or BYL719 in mouse xenograft models either as single agent or in combination with cetuximab. There was no correlation between baseline NRG1 or HER3 phosphorylation level with in vitro LJM716 or BYL719 efficacy. Conclusion: HNSCC is a disease highly dependent on PI3K activity. Mechanisms leading to sustained PI3K activity in HNSCC include genomic changes of PIK3CA/PTEN, activation of HER3 and additional undefined molecular events. Combining HER3/PI3K targeted therapies with cetuximab may overcome some of the resistance to cetuximab therapy in HNSCC. Future work is underway to identify biomarkers that would predict response to these combination regimens. Citation Format: Qing Sheng, HuiQin Wang, Rita Das, Yan Chen, Jinsheng Liang, Alex Cao, Carl Uli Bialucha, Seth Ettenberg, Alan Huang. Targeting HER3 and PI3K in head and neck squamous cancer cells. [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 4261. doi:10.1158/1538-7445.AM2013-4261