Abstract 4113: Acquired resistance to cetuximab is mediated by HER3 activation in head and neck squamous cell carcinoma

Abstract

Abstract Cetuximab, an EGFR monocloanal antibody, is commonly known to be an effective treatment agent in head and neck squamous cell carcinoma (HNSCC). However, despite the clinical efficacy of cetuximab, a majority of patients with good initial response still suffer from side effects as the acquired resistance to cetuximab. To understand the mechanisms of acquired resistance to cetuximab, we developed a model by exposing a head and neck cancer cell line Cal27 to increasing concentrations of cetuximab and established cetuximab-resistant clones (CETr) derived from the cetuximab sensitive (CETp). We examined how the acquired resistance in the CETr influenced the signaling pathway compared to the CETp. We investigated the effect of lapatinib, a tyrosine kinase inhibitor inhibiting HER3, with or without cetuximab combination on CETr clones and in a xenograft mouse model. Cetuximab-resistant(CETr) clones showed robust overexpression on the HER family receptors HER3. CETr clones also expressed upregulated EGFR, HER2, and HER3 activation resulting in activation of PI3K/ATK and ERK signaling. We also showed that CETr clones exhibited increased EGFR/HER3 dimerization. Treatment of cetuximab and siHER3 RNA together reduced EGFR activation in CETr clones to re-sensitize cells against cetuximab and robustly decreased cell proliferation. Combined treatment of CETr clones with cetuximab and lapatinib led to potent anti-proliferative effects. Co-treatment with cetuximab and lapatinib blocked EGFR, HER2 and HER3 activities and inhibited downstream signaling pathways. Co-treatment resulted in suppression of cell growth more effectively than each drug alone and induced apoptotic cell death through mitochondrial ROS. Furthermore, Co-treatment with cetuximab and lapatinib also led to suppression of tumor growth in orthotopic xenograft mouse model of oral tongue cancer. Our results suggested the upregulation of HER3 as a mechanism underlying resistance to cetuximab in HNSCC, supporting further clinical treatment strategy for tumors displaying acquired resistance to cetuximab. Citation Format: Yeon Ju Yang, Min Hee Cho, Yoo Jung Oh, Da Hee Kim, Jung Min Kim, Hyung Kwon Byeon, Myung Jin Ban, Ji Hoon Kim, Jae Wook Kim, Min Hee Ku, Jae Moon Yang, Eun Chang Choi, Yoon Woo Koh, Jeong Yeon Lee. Acquired resistance to cetuximab is mediated by HER3 activation in head and neck squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4113. doi:10.1158/1538-7445.AM2017-4113