Abstract 4476: Therapeutic exploitation of passenger amplifications in hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) represents the predominant primary liver malignancy and the second most common cause of cancer-related death worldwide. Although several advances have been made in HCC screening and diagnosis, the therapeutic treatment of advanced disease at present relies mainly on sorafenib and regorafenib, two multi-kinase inhibitors, which demonstrate limited clinical efficacy. Recently, several genomic studies have unveiled the underlying genomic changes governing HCC development, consisting of mutations in prominent driver genes, as well as copy-number variations (CNVs), such as amplifications and deletions of whole chromosome regions, which exceed by far the frequency of individual mutations. Interestingly, CNVs are considered to mediate clonal expansion due to the presence of oncogenic driver genes, but generally comprise also neutral bystander genes with no implication in neoplastic transformation. While current therapeutic approaches largely aim at targeting mutation-induced dysregulated pathways, strategies targeting CNVs are not thoroughly pursued. We hypothesized that passenger aberrations in genomic amplifications of tumor cells could be therapeutically exploited by providing actionable molecules on the cell surface. To this end, we performed bioinformatic analyses of TCGA CNV data and uncovered a list of cell surface protein (CSP) genes which are frequently amplified in HCC and could be used as potential candidates for a “Trojan-horse” approach in this tumor entity. More specifically, a set of CSP genes was found to be amplified in more than 60% of HCCs, as well as other solid tumors. Genetic perturbations of their expression levels had no effect on the growth and proliferation of HCC cell lines, suggesting their passenger status in the context of this malignancy. Furthermore, amplification of CSP-genes resulted in increased protein expression, which was localized primarily at the plasma membrane. Interestingly, a wide range of normal tissues displayed absent to low cytoplasmic levels of these CSPs as compared to several solid tumors, which exhibited diverse cell surface-associated expression. In addition, pharmacological inhibition of various oncogenic signaling pathways in cancer cells led to significant CSP upregulation at the protein level in the absence of respective genomic amplifications, raising the therapeutic prospect of targeting these proteins as second hits in combination drug regimens. In summary, we have identified several CSPs as potential targets in HCC, which could achieve high tumor specificity while sparing normal tissue when targeted by anti-CSP radioisotope-conjugated antibodies or CSP-specific CAR-T cells. Citation Format: Christos Patsis, Joan Crous-Maso, Ilaria Salvato, Luise Butthof, Rossella Pellegrino, Thomas Longerich, Matthias Gaida, Petros Christopoulos, Darjus Tschaharganeh. Therapeutic exploitation of passenger amplifications in hepatocellular carcinoma [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 4476.