PO-034 Inhibition of lung carcinoma growth and pulmonary metastasis with DIMATE as single agent and in combination with cisplatin

Abstract

IntroductionAberrant cell proliferation in NSCLC causes an aberrant redox state that leads to the production of toxic reactive species and aldehydes. To keep oxidative stress until a threshold, above which oxidative damage can be detrimental to cell viability, cancer cells must actively upregulate multiple antioxidant systems. The aldehyde dehydrogenase (ALDH) gene superfamily encodes enzymes that are critical for certain life processes and detoxification of numerous endogenous and exogenous aldehyde substrates, including pharmaceuticals and environmental pollutants.Material and methodsIn this study, a meta-analysis was conducted based on multiple microarray data from The Cancer Genome Atlas (TCGA) and gene expression omnibus (GEO) repositories, spanning lung adenocarcinoma and lung squamous cell carcinoma datasets. Twenty-six NSCLC cell lines with different oncogenic driver alterations were used to analyse the molecular and cellular consequences of ALDHs inhibition. Preclinical studies with orthotopic xenografts of NSCLC and lung metastatic breast cancer were performed to evaluate the effect of the inhibition of ALDH class 1 and class3 activity on tumour growth.Results and discussionsHere, we found that increased expression of aldehyde dehydrogenase isoenzymes ALDH1A1, ALDH1A3 and ALDH3A1 in human NSCLC tumours has a strong impact on chemotherapy resistance and patient overall survival, correlating with poor prognosis. We showed that inhibition of class 1 and class 3 ALDH activity with the novel irreversible ALDH1/3 inhibitor DIMATE suppresses tumour growth in orthotopic human lung cancer xenograft model and inhibits lung metastasis of human breast cancer in athymic nude mice. Accumulation of HNE-protein adducts and depletion of intracellular GSH are main responsible of DIMATE-induced cell death. Consistently, we found that alteration of tumour redox balance further enhances sensitivity of NSCLC cells to DIMATE. Finally, we demonstrate that the combination of DIMATE with Cisplatin-induced ROS generation in an orthotopic lung cancer model can significantly enhance the cytotoxicity of these two drugs in NSCLC cells with a synergistic promotion of cell death and marginal systemic toxicity in animals.ConclusionTargeting the detoxification machinery of ALDHs constitutes a novel therapeutic avenue for NSCLC. Patients with increased expression of ALDH1 or ALDH3 might greatly benefit from a combination therapy that include drugs interfering with the activity of these enzymes to overcome patient-specific drug resistance.