Abstract
Abstract HER3 is a member of the ErbB family of receptor tyrosine kinases. Aberrant activation of HER3 as a result of HER2 amplification or neuregulin 1 (NRG1) over-expression has been demonstrated to mediate constitutive activation of downstream oncogenic signals. LJM716 is a fully human IgG1 anti-HER3 monoclonal antibody. It locks HER3 in an inactive conformation and prevents HER3 dimerization with other ErbB family members. This unique mode of action enables LJM716 to block both ligand dependent and ligand independent HER3 activation. In search of new indications that may benefit from anti-HER3 therapies, we noted that squamous cell carcinomas (SCC) tend to have relatively higher NRG1 expression as compared to their adenocarcinoma counterparts. Highest NRG1 expression was observed in the lung SCC cell lines in cell line encyclopedia (CLE). A subset of the lung SCC cell lines with high NRG1 expression are moderately sensitive to LJM716, with HER3 activation detected in all of the sensitive lines. Additionally, EGFR activation is consistently observed in our panel of squamous lung carcinoma models. In some cases, activation of HER2 and/or HER3 is also noted. We hypothesize that squamous lung carcinomas may be dependent on signaling through EGFR, HER2 and HER3. To completely block EGFR, HER2-HER3 signaling, we set to test the treatment of LJM716 and Cetixumab in a number of NGR 1 positive squamous lung carcinomas tumor models. Enhanced anti tumor activity of LJM716 and Cetixumab is observed in four out nine tumor models. Analysis of broad activation status of receptor tyrosine kinases (RTK) reveals that a subset of responsive models have activated pEGFR, pHER2 and pHER3. These data suggest that activated HER3 signaling may be important in a subset of lung squamous cell carcinoma. Combination of anti-HER3 and anti EGFR treatment is effective at inhibiting growth in these tumors. Note: This abstract was not presented at the meeting. Citation Format: Maria C. Pinzon-Ortiz, Xianhui Rong, Richard Versace, Qing Sheng, Z. Alexander Cao. Targeting HER3 and EGFR in NRG1 positive and HER3 mutated lung squamous cell carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5320. doi:10.1158/1538-7445.AM2015-5320
Published Version
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