Understanding the influence of radiotherapy in HCC cell lines, alone or when in combination with BCL-2 inhibitors

Abstract

Hepatocellular carcinoma (HCC) is the predominant form of liver cancer, accounting for approximately 90% of all cases. It is the third most common cause of cancer-related mortality worldwide. The development of this disease is associated with several risk factors, including liver inflammatory diseases, such as cirrhosis.

Treatment options for advanced HCC are limited as the majority of patients present with incurable disease. Stereotactic ablative radiotherapy (SBRT) has recently been approved for patients who are not eligible for curative options. SBRT is reported to provide good tumour control, but patients often succumb to recurrent or metastatic disease. This could be due to a cancer's ability to evade cell death. Therefore, there is a significant opportunity for combining SBRT and systemic therapy to improve treatment outcomes. The intrinsic apoptosis pathway plays a crucial role in programmed cell death. Disruption of this pathway can lead to uncontrolled cell division. Therefore, there is untapped potential in combining SBRT with treatments that promote cell death (termed BH3-mimetics).

The aims of this study were to: 1) assess the radiosensitivity of an HCC cell line (Hep53.4) using in vitro clonogenic assays; 2) evaluate the potential synergistic effect of combination SBRT and BH3-mimetic treatment (e.g. ABT263) using in vitro cell viability assays, and 3) examine whether SBRT causes radiation-induced liver disease in vivo in murine models using immunohistochemistry.

Key findings of this study indicate that Hep53.4 cells are radiosensitive and combination treatment with 6Gy irradiation and ABT263, had a synergistic killing effect. Additionally, histological analysis of collagen markers revealed that SBRT effectively spares healthy liver tissue, whilst modifying the tumour collagen deposition compared to non-irradiated tumour controls. While in vitro data displays promising outcomes regarding the synergistic potential of systemic BH3-mimetic therapy and SBRT, further pre-clinical studies are imperative to establish its applicability in the clinical setting.