Varlitinib demonstrates tumor regression and vessel normalization in ErbB-dependent and mutated beta-catenin hepatocellular carcinoma patient-derived xenograft model

Hepatocellular carcinoma (HCC) is the most common form of liver cancer and current therapies such as sorafenib, regorafenib and lenvatinib, prolong median overall survival by less than a year. Hence, there is an urgent need for additional HCC therapies. Varlitinib is a potent, reversible, small molecule pan – HER inhibitor that selectively binds to EGFR, HER2 and HER4. Varlitinib is currently being clinically tested across multiple indications including biliary tract cancer and gastric cancer. In HCC patient – derived xenograft (PDX) models, varlitinib has been shown to mediate potent anti – tumour activities (ASCO 2016). To understand the molecular profiles of HCC PDX sensitive to varlitinib, we studied the ErbB family signalling in 56 HCC PDX models and varlitinib was found to be efficacious in HCC PDX with activated ErbB2 / 3 as well as mutated beta – catenin. In HCC PDX models with activated ErbB2 / 3 , treatment with varlitinib inhibited multiple proliferation and anti – apoptosis pathways including AKT, PI3K and Survivin pathways. In addition, normalisation of blood vessels by varlitinib in the PDX models, as assessed by staining with biotinylated lectin and anti – CD31, also reduced hypoxia in the tumour microenvironment as well as enhanced the infiltration of immune cells. Activating mutations in the Wnt / beta – catenin pathway lead to tumour development in HCC and occur in a subset of HCC tumours. HCC PDX models with beta – catenin mutation were found to be sensitive to varlitinib. Varlitinib led to down – regulation of mutated beta – catenin signalling, and enhanced staining of beta – catenin at the membrane instead of in the nucleus. Since activating mutations in the Wnt / beta – catenin pathway are detected in 26 – 40 % of HCC samples, our data shows that varlitinib may represent an alternative treatment for a significant subset of HCC which are ErbB / beta – catenin – dependent. Citation Format: Wai Ho Shuen, Richard Ong, Chloe Yeo, Rebecca Banu, Lip Seng Koh, Chit Lai Chee, Qihui Seet, Lisa Ooi, Mark McHale, Bertil Lindmark, Han Chong Toh, Huynh Hung. Varlitinib demonstrates tumor regression and vessel normalization in ErbB-dependent and mutated beta-catenin hepatocellular carcinoma patient-derived xenograft model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3992.