Pub Date : 2019-03-04DOI: 10.1146/ANNUREV-CANCERBIO-030518-055914
J. Murai, Y. Pommier
Poly(ADP-ribose) polymerase inhibitors (PARPis) have recently been approved for the treatment of ovarian and breast cancers with BRCA mutations, as well as for maintenance therapies regardless of BRCA mutation for ovarian and primary peritoneal cancers that previously responded to platinum-based chemotherapy. The rationale of these indications is derived from the facts that cancer cells with BRCA mutations are defective in homologous recombination (HR), which confers synthetic lethality with PARPis, and that some of the sensitivity-determining factors for PARPis are shared with platinums. Although BRCA1 and BRCA2 are central for HR, more players within and beyond HR are emerging as response determinants to PARPis. Furthermore, there are similarities as well as differences in the DNA lesions and repair pathways induced by PARPis, platinums, and camptothecin topoisomerase 1 (TOP1) inhibitors. Here we review the sensitivity-determining factors for PARPis and the rationale for using PARPis as single agents and in combination therapy for cancers.
{"title":"PARP Trapping Beyond Homologous Recombination and Platinum Sensitivity in Cancers","authors":"J. Murai, Y. Pommier","doi":"10.1146/ANNUREV-CANCERBIO-030518-055914","DOIUrl":"https://doi.org/10.1146/ANNUREV-CANCERBIO-030518-055914","url":null,"abstract":"Poly(ADP-ribose) polymerase inhibitors (PARPis) have recently been approved for the treatment of ovarian and breast cancers with BRCA mutations, as well as for maintenance therapies regardless of BRCA mutation for ovarian and primary peritoneal cancers that previously responded to platinum-based chemotherapy. The rationale of these indications is derived from the facts that cancer cells with BRCA mutations are defective in homologous recombination (HR), which confers synthetic lethality with PARPis, and that some of the sensitivity-determining factors for PARPis are shared with platinums. Although BRCA1 and BRCA2 are central for HR, more players within and beyond HR are emerging as response determinants to PARPis. Furthermore, there are similarities as well as differences in the DNA lesions and repair pathways induced by PARPis, platinums, and camptothecin topoisomerase 1 (TOP1) inhibitors. Here we review the sensitivity-determining factors for PARPis and the rationale for using PARPis as single agents and in combination therapy for cancers.","PeriodicalId":54233,"journal":{"name":"Annual Review of Cancer Biology-Series","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2019-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1146/ANNUREV-CANCERBIO-030518-055914","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43452722","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-03-04DOI: 10.1146/ANNUREV-CANCERBIO-030518-055636
S. Yum, Minghao Li, A. Frankel, Zhijian J. Chen
Cyclic GMP-AMP synthase (cGAS) is a cytosolic DNA sensor that initiates innate immune responses. DNA-bound cGAS produces cyclic GMP-AMP (cGAMP), which activates stimulator of interferon genes (STING) to induce inflammatory cytokines and other immune mediators. cGAS detects DNA without sequence specificity and responds to both cytosolic foreign DNA from pathogens and self-DNA leaked into the cytosol due to genome instability or cellular damage. Because of the diverse sources of cytosolic DNA, the cGAS-STING pathway plays a critical role during infection, autoimmune diseases, and senescence. Moreover, cGAS detects tumor-derived DNA and stimulates endogenous antitumor immunity. Thus, the cGAS-STING pathway is a promising target for cancer immunotherapy. Here, we review the role of the cGAS-STING pathway in various diseases and highlight various approaches targeting the cGAS-STING pathway for cancer therapy.
{"title":"Roles of the cGAS-STING Pathway in Cancer Immunosurveillance and Immunotherapy","authors":"S. Yum, Minghao Li, A. Frankel, Zhijian J. Chen","doi":"10.1146/ANNUREV-CANCERBIO-030518-055636","DOIUrl":"https://doi.org/10.1146/ANNUREV-CANCERBIO-030518-055636","url":null,"abstract":"Cyclic GMP-AMP synthase (cGAS) is a cytosolic DNA sensor that initiates innate immune responses. DNA-bound cGAS produces cyclic GMP-AMP (cGAMP), which activates stimulator of interferon genes (STING) to induce inflammatory cytokines and other immune mediators. cGAS detects DNA without sequence specificity and responds to both cytosolic foreign DNA from pathogens and self-DNA leaked into the cytosol due to genome instability or cellular damage. Because of the diverse sources of cytosolic DNA, the cGAS-STING pathway plays a critical role during infection, autoimmune diseases, and senescence. Moreover, cGAS detects tumor-derived DNA and stimulates endogenous antitumor immunity. Thus, the cGAS-STING pathway is a promising target for cancer immunotherapy. Here, we review the role of the cGAS-STING pathway in various diseases and highlight various approaches targeting the cGAS-STING pathway for cancer therapy.","PeriodicalId":54233,"journal":{"name":"Annual Review of Cancer Biology-Series","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2019-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1146/ANNUREV-CANCERBIO-030518-055636","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43273978","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-03-04DOI: 10.1146/ANNUREV-CANCERBIO-030518-055719
R. Corcoran
Roughly 70 years after the presence of cell-free DNA (cfDNA) in circulating blood was discovered, cfDNA has emerged as a transformative technology in clinical oncology. The ability to assess the presence, level, and composition of tumor DNA from a routine, noninvasive blood draw has opened the door to a broad array of high-impact clinical applications. While cfDNA is rapidly gaining clinical favor as a means of tumor mutational profiling without the need for an invasive biopsy, emerging applications in the areas of clinical monitoring and early cancer detection hold tremendous promise. These developing applications of cfDNA are reviewed herein.
{"title":"Circulating Tumor DNA: Clinical Monitoring and Early Detection","authors":"R. Corcoran","doi":"10.1146/ANNUREV-CANCERBIO-030518-055719","DOIUrl":"https://doi.org/10.1146/ANNUREV-CANCERBIO-030518-055719","url":null,"abstract":"Roughly 70 years after the presence of cell-free DNA (cfDNA) in circulating blood was discovered, cfDNA has emerged as a transformative technology in clinical oncology. The ability to assess the presence, level, and composition of tumor DNA from a routine, noninvasive blood draw has opened the door to a broad array of high-impact clinical applications. While cfDNA is rapidly gaining clinical favor as a means of tumor mutational profiling without the need for an invasive biopsy, emerging applications in the areas of clinical monitoring and early cancer detection hold tremendous promise. These developing applications of cfDNA are reviewed herein.","PeriodicalId":54233,"journal":{"name":"Annual Review of Cancer Biology-Series","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2019-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1146/ANNUREV-CANCERBIO-030518-055719","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46346198","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-03-04DOI: 10.1146/ANNUREV-CANCERBIO-030518-055855
M. Goncalves, B. Hopkins, L. Cantley
The uncontrolled cellular growth that characterizes tumor formation requires a constant delivery of nutrients. Since the 1970s, researchers have wondered if the supply of nutrients from the diet could impact tumor development. Numerous studies have assessed the impact of dietary components, specifically sugar and fat, to increased cancer risk. For the most part, data from these trials have been inconclusive; however, this does not indicate that dietary factors do not contribute to cancer progression. Rather, the dietary contribution may be dependent on tumor, patient, and context, making it difficult to detect in the setting of large trials. In this review, we combine data from prospective cohort trials with mechanistic studies in mice to argue that fat and sugar can play a role in tumorigenesis and disease progression. We find that certain tumors may respond directly to dietary sugar (colorectal and endometrial cancers) and fat (prostate cancer) or indirectly to the obese state (breast cancer).
{"title":"Dietary Fat and Sugar in Promoting Cancer Development and Progression","authors":"M. Goncalves, B. Hopkins, L. Cantley","doi":"10.1146/ANNUREV-CANCERBIO-030518-055855","DOIUrl":"https://doi.org/10.1146/ANNUREV-CANCERBIO-030518-055855","url":null,"abstract":"The uncontrolled cellular growth that characterizes tumor formation requires a constant delivery of nutrients. Since the 1970s, researchers have wondered if the supply of nutrients from the diet could impact tumor development. Numerous studies have assessed the impact of dietary components, specifically sugar and fat, to increased cancer risk. For the most part, data from these trials have been inconclusive; however, this does not indicate that dietary factors do not contribute to cancer progression. Rather, the dietary contribution may be dependent on tumor, patient, and context, making it difficult to detect in the setting of large trials. In this review, we combine data from prospective cohort trials with mechanistic studies in mice to argue that fat and sugar can play a role in tumorigenesis and disease progression. We find that certain tumors may respond directly to dietary sugar (colorectal and endometrial cancers) and fat (prostate cancer) or indirectly to the obese state (breast cancer).","PeriodicalId":54233,"journal":{"name":"Annual Review of Cancer Biology-Series","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2019-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1146/ANNUREV-CANCERBIO-030518-055855","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48776352","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-03-04DOI: 10.1146/ANNUREV-CANCERBIO-030518-055645
A. Carugo, G. Draetta
The identification and prosecution of meritorious anticancer drug targets and the discovery of clinical candidates represent an extraordinarily time- and resource-intensive process, and the current failure rate of late-stage drugs is a critical issue that must be addressed. Relationships between academia and industry in drug discovery and development have continued to change over time as a result of technical and financial challenges and, most importantly, to the objective of translating impactful scientific discoveries into clinical opportunities. This Golden Age of anticancer drug discovery features an increased appreciation for the high-risk, high-innovation research conducted in the nonprofit sector, with the goals of infusing commercial drug development with intellectual capital and curating portfolios that are financially tenable and clinically meaningful. In this review, we discuss the history of academic-industry interactions in the context of antidrug discovery and offer a view of where these interactions are likely headed as we continue to reach new horizons in our understanding of the immense complexities of cancer biology.
{"title":"Academic Discovery of Anticancer Drugs: Historic and Future Perspectives","authors":"A. Carugo, G. Draetta","doi":"10.1146/ANNUREV-CANCERBIO-030518-055645","DOIUrl":"https://doi.org/10.1146/ANNUREV-CANCERBIO-030518-055645","url":null,"abstract":"The identification and prosecution of meritorious anticancer drug targets and the discovery of clinical candidates represent an extraordinarily time- and resource-intensive process, and the current failure rate of late-stage drugs is a critical issue that must be addressed. Relationships between academia and industry in drug discovery and development have continued to change over time as a result of technical and financial challenges and, most importantly, to the objective of translating impactful scientific discoveries into clinical opportunities. This Golden Age of anticancer drug discovery features an increased appreciation for the high-risk, high-innovation research conducted in the nonprofit sector, with the goals of infusing commercial drug development with intellectual capital and curating portfolios that are financially tenable and clinically meaningful. In this review, we discuss the history of academic-industry interactions in the context of antidrug discovery and offer a view of where these interactions are likely headed as we continue to reach new horizons in our understanding of the immense complexities of cancer biology.","PeriodicalId":54233,"journal":{"name":"Annual Review of Cancer Biology-Series","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2019-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1146/ANNUREV-CANCERBIO-030518-055645","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41566361","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-03-04DOI: 10.1146/ANNUREV-CANCERBIO-030617-050400
S. Guerra, K. Cichowski
While mutations resulting in the chronic activation of signaling pathways drive human cancer, the epigenetic state of a cell ultimately dictates the biological response to any given oncogenic signal. Moreover, large-scale genomic sequencing efforts have now identified a plethora of mutations in chromatin regulatory genes in human tumors, which can amplify, modify, or complement traditional oncogenic events. Nevertheless, the co-occurrence of oncogenic and epigenetic defects appears to create novel therapeutic vulnerabilities, which can be targeted by specific drug combinations. Here we discuss general mechanisms by which oncogenic and epigenetic alterations cooperate in human cancer and synthesize the field's early efforts in developing promising therapeutic combinations. Collectively, these studies reveal common themes underlying potential chemical synthetic lethal interactions and support both the expansion and refinement of this type of therapeutic approach.
{"title":"Targeting Cancer at the Intersection of Signaling and Epigenetics","authors":"S. Guerra, K. Cichowski","doi":"10.1146/ANNUREV-CANCERBIO-030617-050400","DOIUrl":"https://doi.org/10.1146/ANNUREV-CANCERBIO-030617-050400","url":null,"abstract":"While mutations resulting in the chronic activation of signaling pathways drive human cancer, the epigenetic state of a cell ultimately dictates the biological response to any given oncogenic signal. Moreover, large-scale genomic sequencing efforts have now identified a plethora of mutations in chromatin regulatory genes in human tumors, which can amplify, modify, or complement traditional oncogenic events. Nevertheless, the co-occurrence of oncogenic and epigenetic defects appears to create novel therapeutic vulnerabilities, which can be targeted by specific drug combinations. Here we discuss general mechanisms by which oncogenic and epigenetic alterations cooperate in human cancer and synthesize the field's early efforts in developing promising therapeutic combinations. Collectively, these studies reveal common themes underlying potential chemical synthetic lethal interactions and support both the expansion and refinement of this type of therapeutic approach.","PeriodicalId":54233,"journal":{"name":"Annual Review of Cancer Biology-Series","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2019-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1146/ANNUREV-CANCERBIO-030617-050400","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48179751","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-03-04DOI: 10.1146/ANNUREV-CANCERBIO-030518-055653
Jeffrey S. Miller, L. Lanier
Natural killer (NK) cells have evolved to complement T and B cells in host defense against pathogens and cancer. They recognize infected cells and tumors using a sophisticated array of activating, costimulatory, and inhibitory receptors that are expressed on NK cell subsets to create extensive functional diversity. NK cells can be targeted to kill with exquisite antigen specificity by antibody-dependent cellular cytotoxicity. NK and T cells share many of the costimulatory and inhibitory receptors that are currently under evaluation in the clinic for cancer immunotherapy. As with T cells, genetic engineering is being employed to modify NK cells to specifically target them to tumors and to enhance their effector functions. As the selective pressures exerted by immunotherapies to augment CD8+ T cell responses may result in loss of MHC class I, NK cells may provide an important fail-safe to eliminate these tumors by their capacity to eliminate tumors that are “missing self.”
{"title":"Natural Killer Cells in Cancer Immunotherapy","authors":"Jeffrey S. Miller, L. Lanier","doi":"10.1146/ANNUREV-CANCERBIO-030518-055653","DOIUrl":"https://doi.org/10.1146/ANNUREV-CANCERBIO-030518-055653","url":null,"abstract":"Natural killer (NK) cells have evolved to complement T and B cells in host defense against pathogens and cancer. They recognize infected cells and tumors using a sophisticated array of activating, costimulatory, and inhibitory receptors that are expressed on NK cell subsets to create extensive functional diversity. NK cells can be targeted to kill with exquisite antigen specificity by antibody-dependent cellular cytotoxicity. NK and T cells share many of the costimulatory and inhibitory receptors that are currently under evaluation in the clinic for cancer immunotherapy. As with T cells, genetic engineering is being employed to modify NK cells to specifically target them to tumors and to enhance their effector functions. As the selective pressures exerted by immunotherapies to augment CD8+ T cell responses may result in loss of MHC class I, NK cells may provide an important fail-safe to eliminate these tumors by their capacity to eliminate tumors that are “missing self.”","PeriodicalId":54233,"journal":{"name":"Annual Review of Cancer Biology-Series","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2019-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1146/ANNUREV-CANCERBIO-030518-055653","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44740486","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-03-04DOI: 10.1146/ANNUREV-CANCERBIO-030518-055455
A. Levine
Half of all human cancers contain TP53 mutations, and in many other cancers, the function of the p53 protein is compromised. The diversity of these mutations and phenotypes presents a challenge to the development of drugs that target p53 mutant cancer cells. This review describes the rationale for many different approaches in the development of p53 targeted therapies: ( a) viruses and gene therapies, ( b) increased levels and activity of wild-type p53 proteins in cancer cells, ( c) p53 protein gain-of-function inhibitors, ( d) p53 protein loss-of-function structural correctors, ( e) mutant p53 protein synthetic lethal drugs interfering with the p53 pathway, and ( f) cellular immune responses to mutant p53 protein antigens. As these types of therapies are developed, tested, and evaluated, the best of them will have a significant impact upon cancer treatments and possibly prevention.
{"title":"Targeting Therapies for the p53 Protein in Cancer Treatments","authors":"A. Levine","doi":"10.1146/ANNUREV-CANCERBIO-030518-055455","DOIUrl":"https://doi.org/10.1146/ANNUREV-CANCERBIO-030518-055455","url":null,"abstract":"Half of all human cancers contain TP53 mutations, and in many other cancers, the function of the p53 protein is compromised. The diversity of these mutations and phenotypes presents a challenge to the development of drugs that target p53 mutant cancer cells. This review describes the rationale for many different approaches in the development of p53 targeted therapies: ( a) viruses and gene therapies, ( b) increased levels and activity of wild-type p53 proteins in cancer cells, ( c) p53 protein gain-of-function inhibitors, ( d) p53 protein loss-of-function structural correctors, ( e) mutant p53 protein synthetic lethal drugs interfering with the p53 pathway, and ( f) cellular immune responses to mutant p53 protein antigens. As these types of therapies are developed, tested, and evaluated, the best of them will have a significant impact upon cancer treatments and possibly prevention.","PeriodicalId":54233,"journal":{"name":"Annual Review of Cancer Biology-Series","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2019-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1146/ANNUREV-CANCERBIO-030518-055455","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41658128","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-03-04DOI: 10.1146/ANNUREV-CANCERBIO-030518-055533
Alex M. Jaeger, L. Whitesell
The stability and function of many oncogenic mutant proteins depend on heat shock protein 90 (HSP90). This unique activity has inspired the exploration of HSP90 as an anticancer target for over two decades. Unfortunately, while clinical trials of highly optimized HSP90 inhibitors have demonstrated modest benefit for patients with advanced cancers, most commonly stabilization of disease, no HSP90 inhibitor has demonstrated sufficient efficacy to achieve FDA approval to date. This review discusses potential reasons for the limited success of these agents and how our increasingly sophisticated understanding of HSP90 suggests alternative, potentially more effective strategies for targeting it to treat cancers. First, we focus on insights gained from model organisms that suggest a fundamental role for HSP90 in supporting the adaptability and heterogeneity of cancers, key factors underlying their ability to evolve and acquire drug resistance. Second, we examine how HSP90’s role in promoting the stability of mutant proteins might be targeted in genetically unstable tumor cells to reveal their aberrant, foreign proteome to the immune system. Both of these emerging aspects of HSP90 biology suggest that the most effective use of HSP90 inhibitors may not be at high doses with the intent to kill cancer cells, but rather in combination with other molecularly targeted therapies at modest, non-heat shock-inducing exposures that limit the adaptive capacity of cancers.
{"title":"HSP90: Enabler of Cancer Adaptation","authors":"Alex M. Jaeger, L. Whitesell","doi":"10.1146/ANNUREV-CANCERBIO-030518-055533","DOIUrl":"https://doi.org/10.1146/ANNUREV-CANCERBIO-030518-055533","url":null,"abstract":"The stability and function of many oncogenic mutant proteins depend on heat shock protein 90 (HSP90). This unique activity has inspired the exploration of HSP90 as an anticancer target for over two decades. Unfortunately, while clinical trials of highly optimized HSP90 inhibitors have demonstrated modest benefit for patients with advanced cancers, most commonly stabilization of disease, no HSP90 inhibitor has demonstrated sufficient efficacy to achieve FDA approval to date. This review discusses potential reasons for the limited success of these agents and how our increasingly sophisticated understanding of HSP90 suggests alternative, potentially more effective strategies for targeting it to treat cancers. First, we focus on insights gained from model organisms that suggest a fundamental role for HSP90 in supporting the adaptability and heterogeneity of cancers, key factors underlying their ability to evolve and acquire drug resistance. Second, we examine how HSP90’s role in promoting the stability of mutant proteins might be targeted in genetically unstable tumor cells to reveal their aberrant, foreign proteome to the immune system. Both of these emerging aspects of HSP90 biology suggest that the most effective use of HSP90 inhibitors may not be at high doses with the intent to kill cancer cells, but rather in combination with other molecularly targeted therapies at modest, non-heat shock-inducing exposures that limit the adaptive capacity of cancers.","PeriodicalId":54233,"journal":{"name":"Annual Review of Cancer Biology-Series","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2019-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1146/ANNUREV-CANCERBIO-030518-055533","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43911257","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-03-04DOI: 10.1146/ANNUREV-CANCERBIO-030518-055844
S. Dixon, B. Stockwell
Ferroptosis is a nonapoptotic, iron-dependent form of cell death that can be activated in cancer cells by natural stimuli and synthetic agents. Three essential hallmarks define ferroptosis, namely: the loss of lipid peroxide repair capacity by the phospholipid hydroperoxidase GPX4, the availability of redox-active iron, and oxidation of polyunsaturated fatty acid (PUFA)-containing phospholipids. Several processes including RAS/MAPK signaling, amino acid and iron metabolism, ferritinophagy, epithelial-to-mesenchymal transition, cell adhesion, and mevalonate and phospholipid biosynthesis can modulate susceptibility to ferroptosis. Ferroptosis sensitivity is also governed by p53 and KEAP1/NRF2 activity, linking ferroptosis to the function of key tumor suppressor pathways. Together these findings highlight the role of ferroptosis as an emerging concept in cancer biology and an attractive target for precision cancer medicine discovery.
{"title":"The Hallmarks of Ferroptosis","authors":"S. Dixon, B. Stockwell","doi":"10.1146/ANNUREV-CANCERBIO-030518-055844","DOIUrl":"https://doi.org/10.1146/ANNUREV-CANCERBIO-030518-055844","url":null,"abstract":"Ferroptosis is a nonapoptotic, iron-dependent form of cell death that can be activated in cancer cells by natural stimuli and synthetic agents. Three essential hallmarks define ferroptosis, namely: the loss of lipid peroxide repair capacity by the phospholipid hydroperoxidase GPX4, the availability of redox-active iron, and oxidation of polyunsaturated fatty acid (PUFA)-containing phospholipids. Several processes including RAS/MAPK signaling, amino acid and iron metabolism, ferritinophagy, epithelial-to-mesenchymal transition, cell adhesion, and mevalonate and phospholipid biosynthesis can modulate susceptibility to ferroptosis. Ferroptosis sensitivity is also governed by p53 and KEAP1/NRF2 activity, linking ferroptosis to the function of key tumor suppressor pathways. Together these findings highlight the role of ferroptosis as an emerging concept in cancer biology and an attractive target for precision cancer medicine discovery.","PeriodicalId":54233,"journal":{"name":"Annual Review of Cancer Biology-Series","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2019-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1146/ANNUREV-CANCERBIO-030518-055844","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43005267","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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