Defining COMMD4 as an anti-cancer therapeutic target and potential diagnostic biomarker in lung cancer

Introduction: Lung cancer is the most commonly diagnosed cancer worldwide and additionally the most common cause of death from cancer. New therapeutic targets are required as resistance to the current treatments are inevitable. Genomic instability is a hallmark of cancer. In order to prevent cancer, cells possess a complex network of signalling pathways called the DNA damage response, which is involved in the detection, signalling, and subsequent repair of DNA. Failure of the DNA damage response leads to cancer and tumorigenesis. The purpose of this study was to determine the functional relevance and therapeutic potential of a novel player in the DNA damage response, COMMD4, in lung cancer. Methods: The expression of COMMD4 in squamous and non- squamous non-small cell lung cancer was investigated using bioinformatics and immunoblotting experiments from immortalised human bronchial epithelial cell (HBEC) and lung cancer cell lines. The function of COMMD4 in lung cancer was determined using several in vitro assays with the depletion of COMMD4 with small interfering RNA, in HBEC and lung cancer cell lines. Results: In this study, COMMD4 gene transcripts were highly up- regulated in lung cancer versus non-malignant tissue, with high levels of COMMD4 being associated with poor patient prognosis. COMMD4 protein expression levels were also increased in some lung cancer cell lines compared with HBEC cell lines. Cell depleted of COMMD4 were found to be hypersensitive to DNA damaging agents currently used as chemotherapeutic agents in the clinic. Depletion of COMMD4 expression markedly reduced the proliferation of lung cancer cells and not the HBECs. Conclusion: Our findings highlight COMMD4 as a novel anti-cancer therapeutic target and potential diagnostic biomarker in lung cancer, through the induction of cell death and inhibition of tumour growth. Disclosure: All authors have declared no conflicts of interest.