No abstract

Ferroptosis is a novel form of non-apoptotic regulated cell death (RCD), with distinct characteristics and functions in physical conditions and multiple diseases such as cancers. Unlike apoptosis and autophagy, this new RCD is an iron-dependent cell death with features of lethal accumulation of reactive oxygen species (ROS) and over production of lipid peroxidation. Excessive iron from aberrant iron metabolisms or the maladjustment of the two main redox systems thiols and lipid peroxidation role as the major causes of ROS generation, and the redox-acrive ferrous (intracellular labile iron) is a crucial factor for the lipid peroxidation. Regulation of ferrroptosis also involves different pathways such as mevalonate pathway, P53 pathway and p62-Keap1-Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway. Ferroptosis roles as a double-edged sword either suppressing or promoting tumor progression with the release of multiple signaling molecules in the tumor microenvironment. Emerging evidence suggests ferroptosis as a potential target for cancer therapy and ferroptosis inducers including small molecules and nanomaterials have been developed. The application of ferroptosis inducers also relates to overcoming drug resistance and preventing tumor metastasis, and may become a promising strategy combined with other anticancer therapies. Here, we summarize the ferroptosis characters from its underlying basis and role in cancer, followed by its possible applications in cancer therapies and challenges maintained.

Epithelial-to-mesenchymal transition (EMT) has profound impacts on cancer progression and also on drug resistance, including epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). Nowadays, there is still no predictive biomarker identified for the use of EGFR-TKIs in non-small cell lung cancer (NSCLC) patients with wild-type EGFR. To clarify the role of EMT phenotype as a predictive marker for EGFR-TKI, we performed a retrospective study in 202 stage IV or recurrent NSCLC patients receiving gefitinib or erlotinib therapy from June 2008 to September 2012 in our institute. Clinical data and EGFR mutational status were collected, while epithelial, epithelial to mesenchymal, not specified or mesenchymal phenotype were classified according to EMT markers such as E-cadherin, fibronectin, N-cadherin and vimentin by immunohistochemistry. Epithelial phenotype was more frequently found in patients with EGFR mutation (p 5 0.044). Epithelial phenotype was associated with a significantly higher objective response rate (23.5 vs. 11.1 vs. 0.0 vs. 2.4%, p 5 0.011), longer progression-free survival (4.4 vs. 1.9 vs. 1.7 vs. 1.0 months, p < 0.001) and longer overall survival (11.5 vs. 8.9 vs. 4.5 vs. 4.9 months, p < 0.001) compared to epithelial to mesenchymal, not specified and mesenchymal phenotype in the wild-type EGFR subgroup. In the subgroup with EGFR mutation, the trend remained but without a statistically significant difference. In conclusion, epithelial phenotype was more likely expressed in patients with EGFR mutation and was associated with a better outcome in advanced NSCLC patients with wild-type EGFR, which indicates that the EMT phenotype might be a potential marker to guide EGFR-TKI therapy in this population.Tailored therapy based on biomarker analysis has entered reality of lung cancer treatment. Patients with EGFR-activated mutation or ALK/ROS1 fusion gain significant benefit from targeted therapy with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) or ALK inhibitors. However, only a minority of patients express these markers, with EGFR