PO-027 Potential use of BH3 mimetics in the treatment of head and neck cancer

Abstract

IntroductionHead and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. The limited success and significant toxicities associated with current therapies highlight the need for more efficacious treatment strategies. BH3 mimetics are an emerging class of drugs that target the anti-apoptotic BCL-2 family members, which are overexpressed proteins in many cancers, contributing to evasion of apoptosis and resistance to many therapeutic regimens. The BCL-2 specific inhibitor, venetoclax, is currently used to treat haematological malignancies, whereas specific inhibitors for BCL-XL and MCL-1 are entering clinical trials. We aim to determine the potential of BH3 mimetics in the treatment of HNSCC.Material and methodsHNSCC tissue microarrays (TMAs) were immunohistochemically stained for BCL-2, BCL-XL and MCL-1, protein levels assessed semi-quantitatively as low, moderate or high and correlated with patient survival. Cell lines and primary cells were treated with ABT-199 (BCL-2 specific), A1331852 (BCL-XL specific) and/or S63845 (MCL-1 specific), and apoptosis induction and replicative potential were assessed.Results and discussionsTMAs revealed that HNSCC tumours express moderate to high levels of BCL-XL and MCL-1, but low levels of BCL-2. Indeed treatment with a BCL-2 inhibitor had little effect on cell death in HNSCC cell lines; nor did treatment with A1331852 or S63845 as single agents. However, a combination of MCL-1 and BCL-XL inhibition induced extensive apoptotic cell death and a marked reduction in clonogenic cell growth, suggesting a dependence on these two anti-apoptotic proteins for tumour cell survival. A comparison of MCL-1 and BCL-XL expression levels against overall survival of HNSCC patients over a five year period post-surgery revealed that high MCL-1 levels were associated with low median survival. In contrast, the correlation between high BCL-XL expression and median survival was statistically not significant, although it may be clinically relevant.ConclusionBCL-2 is poorly expressed in HNSCC tumours, diminishing the potential of using venetoclax in HNSCC. In contrast, both BCL-XL and MCL-1 are highly expressed in HNSCC, and may be important prognostic indicators. Therefore targeting BCL-XL and MCL-1 together may be therapeutically beneficial, although the toxicity of this combination must be assessed before human trials can be considered.