Abstract 2973: Growth response of human liver cancer cell lines to treatment with various agents targeting different members of the HER family and CDKs
Authors: Ozyamaci Ozlem H. , Seddon Alan M. , Mudan Satvider , Modjtahedi Helmout 
Published: August 2019

Liver cancer is one of the most lethal types of cancer in the world. The heterogeneous nature of liver cancer, together with primary and secondary resistance to existing drugs are some of the important contributing factors. In the past three decades, abnormal expression and activation of human epidermal growth factor receptor (HER) family members have been reported in a wide range of epithelial cancers and several monoclonal antibody (mAb)-based drugs and small molecule tyrosine kinase inhibitors (TKIs) targeting the HER family members have been approved for the treatment of patients with a wide range of cancers. However, none of the HER inhibitors have yet been approved for the treatment of patients with liver cancer. In some studies, the expression of other members of the HER family or other growth factor receptors has been associated with the resistance to therapy with the HER inhibitors. In this study, we investigated the relative expression of all HER family members, other growth factor receptors (e.g. IGF-IR, C-MET) and the putative cancer stem cell biomarker CD44 in a panel of human liver cancer cell lines (LCCLs). We also investigated the sensitivity of these LCCLs to treatment with various agents including different types of TKIs with specificity to one or more members of the HER family, C-MET or IGFI-IR, as well as inhibitors of CDK4/6 (palbocicilib) and CDK1/2/5/9 (dinacicilib) and compared our data to those obtained with the FDA approved agents sorafenib and regorafenib for the treatment of liver cancer. While the great majority of the LCCLs were positive for the HER family members, overexpression of the EGFR, HER-3, and HER-4 were only present in SNU475, PLC/PRF5 and PLC/PRF5 LCCLs with mean fluorescence intensity (MFI) values of 620, 130 and 84 respectively. In contrast, the expression levels of C-MET and IGF-IR were the highest in SNU449 and HEPG-2 with MFI values of 95 and 99 respectively. Four of the seven LCCLs had overexpression of CD44 with the MFI values ranging from 329 to 704. With the exception of PLC/PRF5 which was found to be more sensitive to treatment with the pan-HER TKI afatinib (IC50 = 86nM) than treatment with sorafenib (IC50= 370nM) and regorafenib (372 nM), most of the other LCCLs were insensitive to treatment with the other types of HER inhibitors. Moreover, out of all the targeted therapies, the CDK inhibitors Dinacicilib and Palbocicilib were the most effective treatment for inhibiting the growth in vitro of these LCCLs. However, using linear regression analysis, we did not find any significant association between the expression level of different growth factor receptors and the response to therapy with various agents. Taken together our results show the heterogeneous nature of human LCCLs and the need for further investigation on the therapeutic potential of afatinib in combination with other agents in liver cancer.

Citation Format: Ozlem H. Ozyamaci, Alan M. Seddon, Satvider Mudan, Helmout Modjtahedi. Growth response of human liver cancer cell lines to treatment with various agents targeting different members of the HER family and CDKs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2973.