HS-173

Novel therapeutics are required to improve treatment outcomes in head and neck squamous cell carcinoma (HNSCC) patients. Histone lysine demethylases (KDM) have emerged recently as new potential drug targets for HNSCC therapy. They might also potentiate the action of the inhibitors of EGFR and PI3K signaling pathways. This study aimed at evaluating the anti-cancer effects of KDM4 (ML324) and KDM6 (GSK-J4) inhibitors and their combinations with EGFR (erlotinib) and PI3K (HS-173) inhibitors in HNSCC cells. The effect of the inhibitors on the viability of CAL27 and FaDu cells was evaluated using resazurin assay. The effect of the chemicals on cell cycle and apoptosis was assessed using propidium iodide and Annexin V staining, respectively. The effect of the compounds on gene expression was determined using qPCR and Western blot. The changes in cell cycle distribution upon treatment with the compounds were small to moderate, with the exception of erlotinib, which induced G1 arrest. However, all the compounds and their combinations induced apoptosis in both cell lines. These effects were associated with changes in the level of expression of CDKN1A, CCND1 and BIRC5. The inhibition of KDM4 and KDM6 using ML324 and GSK-J4, respectively, can be regarded as a novel therapeutic strategy in HNSCC.

Ferroptosis is a type of nonapoptotic cell death driven by lipid peroxidation. Here, we show a key role of MGST1 in inhibiting ferroptosis in cell cultures and mouse xenograft models. Ferroptosis activators induce MGST1 upregulation in human pancreatic ductal adenocarcinoma (PDAC) cell lines in an NFE2L2-dependent manner. The genetic depletion of MGST1 or NFE2L2 has a similar effect in promoting ferroptosis, whereas the re-expression of MGST1 restores the resistance of NFE2L2-knockdown cells to ferroptosis. MGST1 inhibits ferroptotic cancer cell death partly by binding to ALOX5, resulting in reduced lipid peroxidation. The expression of MGST1 is positively correlated with NFE2L2 expression in pancreatic tumors, which is implicated in the poor prognosis of patients with PDAC. These findings not only provide a valuable insight into the defense mechanism against ferroptotic cell death, but also indicate that targeting the MGST1 redox-sensitive pathway may be a promising strategy for the treatment of PDAC.