Targeting Regulated Cell Death with Pharmacological Small Molecules: An Update on Autophagy-Dependent Cell Death, Ferroptosis, and Necroptosis in Cancer

Wu, Junhao; Ye, Jing; Xie, Qiang; Liu, Bo; Liu, Ming

doi:10.1021/acs.jmedchem.1c01572

Cited by 41 publications

(37 citation statements)

References 77 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Accumulating evidence has revealed that necroptosis genes play an important role in cancer initiation and progression ( 9 , 10 ). Necroptosis genes are also involved in tumorigenesis, distant metastasis and immunosuppression ( 11 ).…”

Section: Introductionmentioning

confidence: 99%

Identification and analysis of necroptosis-associated signatures for prognostic and immune microenvironment evaluation in hepatocellular carcinoma

Bao

et al. 2022

Front. Immunol.

View full text Add to dashboard Cite

BackgroundHepatocellular carcinoma remains the third most common cause of cancer-related deaths worldwide. Although great achievements have been made in resection, chemical therapies and immunotherapies, the pathogenesis and mechanism of HCC initiation and progression still need further exploration. Necroptosis genes have been reported to play an important role in HCC malignant activities, thus it is of great importance to comprehensively explore necroptosis-associated genes in HCC.MethodsWe chose the LIHC cohort from the TCGA, ICGC and GEO databases for this study. ConsensusClusterPlus was adopted to identify the necroptosis genes-based clusters, and LASSO cox regression was applied to construct the prognostic model based on necroptosis signatures. The GSEA and CIBERSORT algorithms were applied to evaluate the immune cell infiltration level. QPCR was also applied in this study to evaluate the expression level of genes in HCC.ResultsWe identified three clusters, C1, C2 and C3. Compared with C2 and C3, the C1 cluster had the shortest overall survival time and highest immune score. The C1 was samples were significantly enriched in cell cycle pathways, some tumor epithelial-mesenchymal transition related signaling pathways, among others. The DEGs between the 3 clusters showed that C1 was enriched in cell cycle, DNA replication, cellular senescence, and p53 signaling pathways. The LASSO cox regression identified KPNA2, SLC1A5 and RAMP3 as prognostic model hub genes. The high risk-score subgroup had an elevated expression level of immune checkpoint genes and a higher TIDE score, which suggested that the high risk-score subgroup had a lower efficiency of immunotherapies. We also validated that the necroptosis signatures-based risk-score model had powerful prognosis prediction ability.ConclusionBased on necroptosis-related genes, we classified patients into 3 clusters, among which C1 had significantly shorter overall survival times. The proposed necroptosis signatures-based prognosis prediction model provides a novel approach in HCC survival prediction and clinical evaluation.

show abstract

Section: Introductionmentioning

confidence: 99%

Identification and analysis of necroptosis-associated signatures for prognostic and immune microenvironment evaluation in hepatocellular carcinoma

Bao

et al. 2022

Front. Immunol.

View full text Add to dashboard Cite

show abstract

“…Furthermore, small molecules, including Imatinib, Bexarotene, Midostaurin, FH535, CGP.082996, CMK, PF.4708671, JW.7.52.1, KIN001.135 and Z.LLNle.CHO also had more significant benefits in high-risk patients. Recent research confirmed that targeting necroptosis with small molecules is a promising strategy for cancer therapy, which may be the key to overcoming apoptosis resistance, and has advantages in overcoming apoptosis resistance and stimulating antitumor immunity (36). Therefore, we believe that the NRGscore can help identify better treatment strategies for individual patients with advanced BLCA.…”

Section: Discussionmentioning

confidence: 99%

Analysis and Identification of Necroptosis Landscape on Therapy and Prognosis in Bladder Cancer

Zhao

Jiang

Zhang

et al. 2022

Preprint

View full text Add to dashboard Cite

Bladder cancer (BLCA) is one of the most common malignant tumors of the urinary system, but current therapeutic strategy based on chemotherapy and immune checkpoint inhibitors (ICIs) therapy cannot meet the treatment needs, which mainly owing to the endogenous or acquired apoptotic resistance of cancer cells. Targeting necroptosis provides a novel strategy for chemotherapy, targeted drugs, and improves the efficacy of ICIs because of strong immunogenicity of necroptosis. Therefore, we systemically analyzed necroptosis landscape on therapy and prognosis in BLCA. We firstly divided BLCA patients from The Cancer Genome Atlas (TCGA) database into two necroptosis-related clusters (C1 and C2). Necroptosis C2 showed a significantly better prognosis than C1, and the differential genes of C2 and C1 were mainly related to the immune response according to GO and KEGG analysis. Next, we constructed a novel necroptosis related genes (NRGs) signature consisting of SIRT6, FASN, GNLY, FNDC4, SRC, ANXA1, AIM2, and IKBKB to predict the survival of TCGA-BLCA cohort, the accuracy of NRGsocre was also verified by external datasets. In addition, a nomogram combining NRGscore and several clinicopathological features was established to predict the BLCA patient’s OS more accurately and conveniently. We also found that NRGscore was significantly related to the infiltration levels of CD8 T cells, NK cells, and iDC cells, the gene expression of CTLA4, PD1, TIGIT, and LAG3 of TME, the sensitivity to chemotherapy and targeted agents in BLCA patients. In conclusion, the NRGscore has an excellent performance in evaluating the prognosis, clinicopathologic features, tumor microenvironment (TME) and therapeutic sensitivity of BLCA patients, which could be utilized as a guide for chemotherapy, ICIs therapy, and combination therapy.

show abstract

“…Furthermore, small molecules, including imatinib, bexarotene, and midostaurin, FH535, CGP.082996, CMK, PF.4708671, JW.7.52.1, KIN001.135, and Z. LLNle.CHO also had more significant benefits in high-risk patients. Recent research confirmed that targeting necroptosis with small molecules is a promising strategy for cancer therapy, which may be the key for overcoming apoptosis resistance, and has advantages in overcoming apoptosis resistance and stimulating antitumor immunity ( Wu J. et al, 2022 ). Therefore, we believe that the NRG score can help identify better treatment strategies for individual patients with advanced BLCA.…”

Section: Discussionmentioning

confidence: 99%

Analysis and identification of the necroptosis landscape on therapy and prognosis in bladder cancer

Zhao

Jiang²,

Zhang³

et al. 2022

Front. Genet.

View full text Add to dashboard Cite

Bladder cancer (BLCA) is one of the most common malignant tumors of the urinary system, but the current therapeutic strategy based on chemotherapy and immune checkpoint inhibitor (ICI) therapy cannot meet the treatment needs, mainly owing to the endogenous or acquired apoptotic resistance of cancer cells. Targeting necroptosis provides a novel strategy for chemotherapy and targeted drugs and improves the efficacy of ICIs because of strong immunogenicity of necroptosis. Therefore, we systemically analyzed the necroptosis landscape on therapy and prognosis in BLCA. We first divided BLCA patients from The Cancer Genome Atlas (TCGA) database into two necroptosis-related clusters (C1 and C2). Necroptosis C2 showed a significantly better prognosis than C1, and the differential genes of C2 and C1 were mainly related to the immune response according to GO and KEGG analyses. Next, we constructed a novel necroptosis-related gene (NRG) signature consisting of SIRT6, FASN, GNLY, FNDC4, SRC, ANXA1, AIM2, and IKBKB to predict the survival of TCGA-BLCA cohort, and the accuracy of the NRG score was also verified by external datasets. In addition, a nomogram combining NRG score and several clinicopathological features was established to more accurately and conveniently predict the BLCA patient’s survival. We also found that the NRG score was significantly related to the infiltration levels of CD8 T cells, NK cells, and iDC cells, the gene expression of CTLA4, PD-1, TIGIT, and LAG3 of TME, and the sensitivity to chemotherapy and targeted agents in BLCA patients. In conclusion, the NRG score has an excellent performance in evaluating the prognosis, clinicopathologic features, tumor microenvironment (TME), and therapeutic sensitivity of BLCA patients, which could be utilized as a guide for chemotherapy, ICI therapy, and combination therapy.

show abstract

Targeting Regulated Cell Death with Pharmacological Small Molecules: An Update on Autophagy-Dependent Cell Death, Ferroptosis, and Necroptosis in Cancer

Cited by 41 publications

References 77 publications

Identification and analysis of necroptosis-associated signatures for prognostic and immune microenvironment evaluation in hepatocellular carcinoma

Identification and analysis of necroptosis-associated signatures for prognostic and immune microenvironment evaluation in hepatocellular carcinoma

Analysis and Identification of Necroptosis Landscape on Therapy and Prognosis in Bladder Cancer

Analysis and identification of the necroptosis landscape on therapy and prognosis in bladder cancer

Contact Info

Product

Resources

About