Ferroptosis is an intracellular iron-dependent form of cell death that is distinct from apoptosis, necrosis, and autophagy. Extensive studies suggest that ferroptosis plays a pivotal role in tumor suppression, thus providing new opportunities for cancer therapy. The development of resistance to cancer therapy remains a major challenge. A number of preclinical and clinical studies have focused on overcoming drug resistance. Intriguingly, ferroptosis has been correlated with cancer therapy resistance, and inducing ferroptosis has been demonstrated to reverse drug resistance. Herein, we provide a detailed description of the mechanisms of ferroptosis and the therapeutic role of regulating ferroptosis in reversing the resistance of cancer to common therapies, such as chemotherapy, targeted therapy and immunotherapy. We discuss the prospect and challenge of regulating ferroptosis as a therapeutic strategy for reversing cancer therapy resistance and expect that our review could provide some references for further studies.

Gefitinib, a tyrosine kinase inhibitor of epidermal growth factor receptor, has been used as the first choice of treatment for advanced non-small-cell lung cancer. However, during the course of treatment, cancer cells often develop resistance to gefitinib without fully understood mechanisms. In this study, we aimed to elucidate an important role of long intergenic non-coding RNA 00665 in developing resistance to gefitinib in non-small-cell lung cancer. We showed that long intergenic non-coding RNA 00665 expression was significantly upregulated in lung cancer tissues and cells with acquired gefitinib resistance. Long intergenic non-coding RNA 00665 knockdown restored gefitinib sensitivity both in vitro and in vivo by suppressing cell proliferation and inducing apoptosis. Moreover, knockdown of long intergenic non-coding RNA 00665 markedly reduced activation of EGFR and its downstream event protein kinase B (AKT). Moreover, LINC00665 could interact with EZH2 and regulate the phosphatidylinositol 3-kinase (PI3K)/AKT pathway. Thus, our study suggests that long intergenic non-coding RNA 00665 is important for non-small-cell lung cancer to develop drug resistance and might be a potential biomarker for drug resistance and a therapeutic target for non-small-cell lung cancer.

Background:In recent years, long non-coding RNAs (lncRNAs) have been shown to be a novel class of regulators of cancer biological processes. Although lncRNAs are dysregulated in numerous cancer types, limited data are available on the expression profiles and potential functions of lncRNAs in lung adenocarcinoma (LUAD). This study evaluated the expression and biological roles of lncRNA SOX21 antisense RNA 1 (SOX21-AS1) in LUAD. Methods: Quantitative reverse transcription PCR (qRT-PCR) was performed to detect the expression levels of SOX21-AS1 in 68 pairs of LUAD tissues and corresponding non-tumor tissues. The effect of SOX21-AS1 on proliferation was evaluated by MTT, colony formation, EdU assays, flow-cytometric analysis and in vivo tumor formation assays. Real-time PCR, western-blot and immunohistochemistry were used to evaluate the mRNA and protein expression of p57. Results: Higher expression levels of SOX21-AS1 positively correlated with tumor size and advanced tumor-node-metastasis (TNM) stage. Multivariate analyses indicated that SOX21-AS1 expression could serve as an independent prognostic factor for overall survival of LUAD. Furthermore, knockdown of SOX21-AS1 significantly inhibited LUAD cell proliferation both in vitro and in vivo and induced cell cycle phase arrest and cell apoptosis. Importantly, through qRT-PCR and western blot analysis, we found that inhibition of SOX21-AS1 remarkably induced p57 expression. Conclusions: Collectively, our study demonstrates that SOX21-AS1 is involved in the development and progression of LUAD and that SOX21-AS1 may be a potential diagnostic factor as well as a target for new therapies for patients with LUAD.X. Lu, C. Huang and X. He contributed equally to this work.

Growth differentiation factor 15 (GDF15), a member of the TGF-β superfamily of cytokines, has been reported to exert very heterogeneous functions in various tumors. However, its expression and roles in mediating non-small-cell lung cancer (NSCLC) progression remain unknown. In this study, we found that GDF15 is downregulated in paired NSCLC tissues and correlated with poor clinical outcomes in NSCLC. A functional experiment demonstrated that overexpression of GDF15 significantly repressed NSCLC proliferation both in vitro and in vivo. Mechanistic studies reveal that inhibition of EZH2 expression prevented its binding to the GDF15 promoter region and reduced the trimethylation modification pattern of H3K27. Together, our data uncover that GDF15 is a direct target of EZH2 and, as a regulator of proliferation, might serve as a candidate prognostic biomarker and target for new therapies in human NSCLC.

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Immune checkpoint inhibitors (ICIs) have exhibited promising efficacy in non-small cell lung cancer (NSCLC), but the response occurs in only a minority of patients. In clinic, biomarkers such as TMB (tumor mutation burden) and PD-L1 (programmed cell death 1 ligand 1) still have their limitations in predicting the prognosis of ICI treatment. Hence, reliable predictive markers for ICIs are urgently needed. A public immunotherapy dataset with clinical information and mutational data of 75 NSCLC patients was obtained from cBioPortal as the discovery cohort, and another immunotherapy dataset of 249 patients across multiple cancer types was collected as the validation. Integrated bioinformatics analysis was performed to explore the potential mechanism, and immunohistochemistry studies were used to verify it. AHNAK nucleoprotein 2 (AHNAK2) was reported to have pro-tumor growth effects across multiple cancers, while its role in tumor immunity was unclear. We found that approximately 11% of the NSCLC patients harbored AHNAK2 mutations, which were associated with promising outcomes to ICI treatments (ORR, p = 0.013). We further found that AHNAK2 deleterious mutation (del-AHNAK2mut) possessed better predictive function in NSCLC than non-deleterious AHNAK2 mutation (PFS, OS, log-rank p < 0.05), potentially associated with stronger tumor immunogenicity and an activated immune microenvironment. This work identified del-AHNAK2mut as a novel biomarker to predict favorable ICI response in NSCLC.

Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI, such as gefitinib) in lung cancer continues to be a major problem. Recent studies have shown the promise of ferroptosis-inducing therapy in EGFR-TKI resistant cancer, but have not been translated into clinical benefits. Here, we identified carbonic anhydrase IX (CA9) was upregulated in gefitinib-resistant lung cancer. Then we measured the cell viability, intracellular reactive oxygen species (ROS) levels, and labile iron levels after the treatment of ferroptosis inducer erastin. We found that CA9 confers resistance to ferroptosis-inducing drugs. Mechanistically, CA9 is involved in the inhibition of transferrin endocytosis and the stabilization of ferritin, leading to resistance to ferroptosis. Targeting CA9 promotes iron uptake and release, thus triggering gefitinib-resistant cell ferroptosis. Notably, CA9 inhibitor enhances the ferroptosis-inducing effect of cisplatin on gefitinib-resistant cells, thus eliminating resistant cells in heterogeneous tumor tissues. Taken together, CA9-targeting therapy is a promising approach to improve the therapeutic effect of gefitinib-resistant lung cancer by inducing ferroptosis.