Abstract 5421: HER3 inhibition has little efficacy on hepatocellular carcinoma cell lines

Abstract

Abstract Background: HER3 is a member of the ErbB family of receptor tyrosine kinases that are involved in the pathogenesis of many malignancies, including hepatocellular carcinoma (HCC) (Hsieh et al: Hepatology 2011). When bound with neuregulins (NRGs) or in the presence of HER2 amplification, HER3 dimerizes with HER2 and activates the signaling transduction cascade. We planned this study to evaluate the efficacy of HER3 inhibition by an anti-HER3 monoclonal antibody, LJM716 (Novartis®), in HCC. Methods: Human HCC cell lines Huh7, HepG2, PLC5, Hep3B, and SK-Hep1 were used in the experiments. We used the quantitative RT-PCR to evaluate the mRNA expression levels of HER2, HER3 and NRGs in HCC cell lines. We used the MTT assay to evaluate the growth inhibitory efficacy of LJM716 alone or in combination with sorafenib, and used the Western blotting to study the expression phospho-HER3 downregulated by LJM716 in these cells. Results: None of the HCC cell lines have HER2 amplification. Huh7 and HepG2 had higher HER2 expression, SK-Hep1 had lower HER3 expression, SK-Hep1 and Hep3B had higher NRG1 and NRG2 expression, and PLC5 had higher NRG2 but not NRG1 expression compared with other HCC cells. In HCC cells cultured with ordinary serum-containing medium, we found LJM716 up to 20 μg/ml showed little suppressive effect in the proliferation of HCC cells; in HCC cells cultured in the presence of NRG1, LJM716 could induce a 20 to 30% growth-suppressive effect at best. LJM716 inhibited NRG1-induced phosphorylation of HER3 in HCC cells dose-dependently. The treatment of sorafenib slightly increased RNA expression levels of NRG1 and HER2 in PLC5, Huh-7, and HepG2 cells. We combined LJM716 and sorafenib to evaluate their combination effect in HCC cells, but found that LJM716 failed to show any synergistic effect to sorafenib. Conclusions: Despite inhibitory effect on HER3 phosphorylation, LJM716 showed minimal therapeutic efficacy on HCC cell lines, either alone or in combination with sorafenib. Citation Format: Yong-Shi Li, Yu-Yun Shao, Han-Yu Wang, Ann-Lii Cheng, Chih-Hung Hsu. HER3 inhibition has little efficacy on hepatocellular carcinoma cell lines. [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 5421. doi:10.1158/1538-7445.AM2015-5421