Pub Date : 2023-12-06DOI: 10.1146/annurev-cancerbio-062822-030450
Daniel A. Bonsor, Dhirendra K. Simanshu
Mutations in RAS proteins play a pivotal role in the development of human cancers, driving persistent RAF activation and deregulating the mitogen-activated protein kinase (MAPK) signaling pathway. While progress has been made in targeting specific oncogenic RAS proteins, effective drug-based therapies for most RAS mutations remain limited. Recent investigations into RAS–RAF complexes and the SHOC2–MRAS–PP1C holoenzyme complex have provided crucial insights into the structural and functional aspects of RAF activation within the MAPK signaling pathway. Moreover, these studies have also unveiled new blueprints for developing inhibitors, allowing us to think beyond the current RAS and MEK inhibitors. In this review, we explore the roles of RAS and SHOC2 in activating RAF and discuss potential therapeutic strategies to target these proteins. A comprehensive understanding of the molecular interactions involved in RAF activation and their therapeutic implications can potentially drive innovative approaches in combating RAS-/RAF-driven cancers.Expected final online publication date for the Annual Review of Cancer Biology, Volume 8 is April 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
{"title":"RAS and SHOC2 Roles in RAF Activation and Therapeutic Considerations","authors":"Daniel A. Bonsor, Dhirendra K. Simanshu","doi":"10.1146/annurev-cancerbio-062822-030450","DOIUrl":"https://doi.org/10.1146/annurev-cancerbio-062822-030450","url":null,"abstract":"Mutations in RAS proteins play a pivotal role in the development of human cancers, driving persistent RAF activation and deregulating the mitogen-activated protein kinase (MAPK) signaling pathway. While progress has been made in targeting specific oncogenic RAS proteins, effective drug-based therapies for most RAS mutations remain limited. Recent investigations into RAS–RAF complexes and the SHOC2–MRAS–PP1C holoenzyme complex have provided crucial insights into the structural and functional aspects of RAF activation within the MAPK signaling pathway. Moreover, these studies have also unveiled new blueprints for developing inhibitors, allowing us to think beyond the current RAS and MEK inhibitors. In this review, we explore the roles of RAS and SHOC2 in activating RAF and discuss potential therapeutic strategies to target these proteins. A comprehensive understanding of the molecular interactions involved in RAF activation and their therapeutic implications can potentially drive innovative approaches in combating RAS-/RAF-driven cancers.Expected final online publication date for the Annual Review of Cancer Biology, Volume 8 is April 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.","PeriodicalId":501431,"journal":{"name":"Annual Review of Cancer Biology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138534799","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-06DOI: 10.1146/annurev-cancerbio-062822-120857
Albert M. Li, Jiangbin Ye
A century ago, Otto Heinrich Warburg made a seminal discovery now known as the Warburg effect. This metabolic signature, prevalent across all cancer cells, is characterized by the prominent shift of glucose metabolism toward lactate production instead of oxidative respiration. Warburg's pioneering theory suggested that the induction of the Warburg effect instigates dedifferentiation and the process of tumorigenesis, illuminating a fundamental mechanism underlying cancer development. To celebrate the centennial anniversary of Warburg's monumental finding, it is an appropriate moment to reflect upon and commemorate his revolutionary contributions to the fields of metabolism and cancer research. In this review, we explore the role of mitochondria in epigenetic regulation and the decisions governing cell fate from an evolutionary standpoint. Moreover, we summarize metabolic and genetic factors that trigger the Warburg effect, underscoring the therapeutic potential of mitochondrial uncoupling as a strategy to counter this metabolic aberration. Our goal is to elucidate the means to induce tumor differentiation through metabolic therapy, thereby laying a foundation toward the cure for cancer.Expected final online publication date for the Annual Review of Cancer Biology, Volume 8 is April 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
{"title":"Deciphering the Warburg Effect: Metabolic Reprogramming, Epigenetic Remodeling, and Cell Dedifferentiation","authors":"Albert M. Li, Jiangbin Ye","doi":"10.1146/annurev-cancerbio-062822-120857","DOIUrl":"https://doi.org/10.1146/annurev-cancerbio-062822-120857","url":null,"abstract":"A century ago, Otto Heinrich Warburg made a seminal discovery now known as the Warburg effect. This metabolic signature, prevalent across all cancer cells, is characterized by the prominent shift of glucose metabolism toward lactate production instead of oxidative respiration. Warburg's pioneering theory suggested that the induction of the Warburg effect instigates dedifferentiation and the process of tumorigenesis, illuminating a fundamental mechanism underlying cancer development. To celebrate the centennial anniversary of Warburg's monumental finding, it is an appropriate moment to reflect upon and commemorate his revolutionary contributions to the fields of metabolism and cancer research. In this review, we explore the role of mitochondria in epigenetic regulation and the decisions governing cell fate from an evolutionary standpoint. Moreover, we summarize metabolic and genetic factors that trigger the Warburg effect, underscoring the therapeutic potential of mitochondrial uncoupling as a strategy to counter this metabolic aberration. Our goal is to elucidate the means to induce tumor differentiation through metabolic therapy, thereby laying a foundation toward the cure for cancer.Expected final online publication date for the Annual Review of Cancer Biology, Volume 8 is April 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.","PeriodicalId":501431,"journal":{"name":"Annual Review of Cancer Biology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138534863","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-06DOI: 10.1146/annurev-cancerbio-062722-013740
Alexander Scheiter, Li-Chun Lu, Lilian H. Gao, Gen-Sheng Feng
The nonreceptor tyrosine phosphatase SHP2 has been at the center of cell signaling research for three decades. SHP2 is required to fully activate the RTK/RAS/ERK signaling cascade, although the underlying mechanisms are not completely understood. PTPN11 , which encodes SHP2, is the first identified proto-oncogene that encodes a tyrosine phosphatase, with dominantly activating mutations detected in leukemias and solid tumors. However, SHP2 has pro- and antioncogenic effects, and the most recent data reveal opposite activities of SHP2 in tumor cells and microenvironment cells. Allosteric SHP2 inhibitors show promising antitumor effects and overcome resistance to inhibitors of RAS/ERK signaling in animal models. Many clinical trials with orally bioactive SHP2 inhibitors, alone or combined with other regimens, are ongoing for a variety of cancers worldwide, with therapeutic outcomes yet unknown. This review discusses the multifaceted functions of SHP2 in oncogenesis, preclinical studies, and clinical trials with SHP2 inhibitors in oncological treatment.Expected final online publication date for the Annual Review of Cancer Biology, Volume 8 is April 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
{"title":"Complex Roles of PTPN11/SHP2 in Carcinogenesis and Prospect of Targeting SHP2 in Cancer Therapy","authors":"Alexander Scheiter, Li-Chun Lu, Lilian H. Gao, Gen-Sheng Feng","doi":"10.1146/annurev-cancerbio-062722-013740","DOIUrl":"https://doi.org/10.1146/annurev-cancerbio-062722-013740","url":null,"abstract":"The nonreceptor tyrosine phosphatase SHP2 has been at the center of cell signaling research for three decades. SHP2 is required to fully activate the RTK/RAS/ERK signaling cascade, although the underlying mechanisms are not completely understood. PTPN11 , which encodes SHP2, is the first identified proto-oncogene that encodes a tyrosine phosphatase, with dominantly activating mutations detected in leukemias and solid tumors. However, SHP2 has pro- and antioncogenic effects, and the most recent data reveal opposite activities of SHP2 in tumor cells and microenvironment cells. Allosteric SHP2 inhibitors show promising antitumor effects and overcome resistance to inhibitors of RAS/ERK signaling in animal models. Many clinical trials with orally bioactive SHP2 inhibitors, alone or combined with other regimens, are ongoing for a variety of cancers worldwide, with therapeutic outcomes yet unknown. This review discusses the multifaceted functions of SHP2 in oncogenesis, preclinical studies, and clinical trials with SHP2 inhibitors in oncological treatment.Expected final online publication date for the Annual Review of Cancer Biology, Volume 8 is April 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.","PeriodicalId":501431,"journal":{"name":"Annual Review of Cancer Biology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138548485","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-04-11DOI: 10.1146/annurev-cancerbio-070220-111016
Annette Paschen, Ignacio Melero, Antoni Ribas
Resistance to immunotherapy is due in some instances to the acquired stealth mechanisms of tumor cells that lose expression of MHC class I antigen–presenting molecules or downregulate their class I antigen–presentation pathways. Most dramatically, biallelic β2-microglobulin (B2M) loss leads to complete loss of MHC class I expression and to invisibility to CD8+ T cells. MHC class I expression and antigen presentation are potently upregulated by interferon-γ (IFNγ) in a manner that depends on IFNγ receptor (IFNGR) signaling via JAK1 and JAK2. Mutations in these molecules lead to IFNγ unresponsiveness and mediate loss of recognition and killing by cytotoxic T lymphocytes. Loss of MHC class I augments sensitivity of tumor cells to be killed by natural killer (NK) lymphocytes, and this mechanism could be exploited to revert resistance, for instance, with interleukin-2 (IL-2)-based agents. Moreover, in some experimental models,potent local type I interferon responses, such as those following intratumoral injection of Toll-like receptor 9 (TLR9) or TLR3 agonists, revert resistance due to mutations of JAKs.
{"title":"Central Role of the Antigen-Presentation and Interferon-γ Pathways in Resistance to Immune Checkpoint Blockade","authors":"Annette Paschen, Ignacio Melero, Antoni Ribas","doi":"10.1146/annurev-cancerbio-070220-111016","DOIUrl":"https://doi.org/10.1146/annurev-cancerbio-070220-111016","url":null,"abstract":"<p>Resistance to immunotherapy is due in some instances to the acquired stealth mechanisms of tumor cells that lose expression of MHC class I antigen–presenting molecules or downregulate their class I antigen–presentation pathways. Most dramatically, biallelic β2-microglobulin (B2M) loss leads to complete loss of MHC class I expression and to invisibility to CD8<sup>+</sup> T cells. MHC class I expression and antigen presentation are potently upregulated by interferon-γ (IFNγ) in a manner that depends on IFNγ receptor (IFNGR) signaling via JAK1 and JAK2. Mutations in these molecules lead to IFNγ unresponsiveness and mediate loss of recognition and killing by cytotoxic T lymphocytes. Loss of MHC class I augments sensitivity of tumor cells to be killed by natural killer (NK) lymphocytes, and this mechanism could be exploited to revert resistance, for instance, with interleukin-2 (IL-2)-based agents. Moreover, in some experimental models,potent local type I interferon responses, such as those following intratumoral injection of Toll-like receptor 9 (TLR9) or TLR3 agonists, revert resistance due to mutations of JAKs.","PeriodicalId":501431,"journal":{"name":"Annual Review of Cancer Biology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138534862","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-01-18DOI: 10.1146/annurev-cancerbio-070620-094029
Cheng-Zhong Zhang, David Pellman
Analysis of cancer genomes has shown that a large fraction of chromosomal changes originate from catastrophic events including whole-genome duplication, chromothripsis, breakage-fusion-bridge cycles, and chromoplexy. Through sophisticated computational analysis of cancer genomes and experimental recapitulation of these catastrophic alterations, we have gained significant insights into the origin, mechanism, and evolutionary dynamics of cancer genome complexity. In this review, we summarize this progress and survey the major unresolved questions, with particular emphasis on the relative contributions of chromosome fragmentation and DNA replication errors to complex chromosomal alterations.
{"title":"Cancer Genomic Rearrangements and Copy Number Alterations from Errors in Cell Division","authors":"Cheng-Zhong Zhang, David Pellman","doi":"10.1146/annurev-cancerbio-070620-094029","DOIUrl":"https://doi.org/10.1146/annurev-cancerbio-070620-094029","url":null,"abstract":"Analysis of cancer genomes has shown that a large fraction of chromosomal changes originate from catastrophic events including whole-genome duplication, chromothripsis, breakage-fusion-bridge cycles, and chromoplexy. Through sophisticated computational analysis of cancer genomes and experimental recapitulation of these catastrophic alterations, we have gained significant insights into the origin, mechanism, and evolutionary dynamics of cancer genome complexity. In this review, we summarize this progress and survey the major unresolved questions, with particular emphasis on the relative contributions of chromosome fragmentation and DNA replication errors to complex chromosomal alterations.","PeriodicalId":501431,"journal":{"name":"Annual Review of Cancer Biology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138534798","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-01-18DOI: 10.1146/annurev-cancerbio-080421-015537
Xue-Yan He, David Ng, Mikala Egeblad
Neutrophil extracellular traps (NETs) are meshes of DNA decorated with granular proteins that are extruded from neutrophils during immune responses to pathogens. However, excessive NET formation is negatively associated with many diseases, including cancer. NETs contain, for example, proteases, danger-associated molecular patterns (DAMPs), and DNA. These components can act directly on the cancer cells but also affect the surrounding microenvironment, including altering the extracellular matrix and the immune response to tumors. Here, we discuss the emerging roles of NETs in cancer progression, from their ability to promote primary tumor growth and immune escape to their prometastatic effects. The potential clinical implication of targeting NETs as novel therapeutic strategies in cancer is also discussed.
{"title":"Caught in a Web: Emerging Roles of Neutrophil Extracellular Traps in Cancer","authors":"Xue-Yan He, David Ng, Mikala Egeblad","doi":"10.1146/annurev-cancerbio-080421-015537","DOIUrl":"https://doi.org/10.1146/annurev-cancerbio-080421-015537","url":null,"abstract":"Neutrophil extracellular traps (NETs) are meshes of DNA decorated with granular proteins that are extruded from neutrophils during immune responses to pathogens. However, excessive NET formation is negatively associated with many diseases, including cancer. NETs contain, for example, proteases, danger-associated molecular patterns (DAMPs), and DNA. These components can act directly on the cancer cells but also affect the surrounding microenvironment, including altering the extracellular matrix and the immune response to tumors. Here, we discuss the emerging roles of NETs in cancer progression, from their ability to promote primary tumor growth and immune escape to their prometastatic effects. The potential clinical implication of targeting NETs as novel therapeutic strategies in cancer is also discussed.","PeriodicalId":501431,"journal":{"name":"Annual Review of Cancer Biology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138534861","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-01-18DOI: 10.1146/annurev-cancerbio-070120-092840
Letian Zhang, David W. Goodrich
Lineage plasticity, a cell's capacity to switch lineage-restricted gene expression states, is required for normal tissue homeostasis. Cancer lineage plasticity is increasingly observed as a mechanism of resistance to therapy, particularly molecularly targeted therapies. These therapies often owe their superior efficacy to the lineage-restricted nature of their therapeutic target, so cancers can evade such therapies by changing lineage states. As increasingly effective molecularly targeted therapies are deployed, cancer lineage plasticity is likely to be a growing clinical problem. Lineage plasticity reflects a nongenetic, potentially reversible transcriptional adaptation, but oncogenic genetic mutations likely drive elevated lineage plasticity that is typical of cancer cells. Here key concepts relevant to cancer lineage plasticity are presented, evidence implicating loss of the RB1 tumor-suppressor gene in driving cancer lineage plasticity is reviewed, and possible therapeutic approaches to counter cancer lineage plasticity are discussed.
{"title":"RB1, Cancer Lineage Plasticity, and Therapeutic Resistance","authors":"Letian Zhang, David W. Goodrich","doi":"10.1146/annurev-cancerbio-070120-092840","DOIUrl":"https://doi.org/10.1146/annurev-cancerbio-070120-092840","url":null,"abstract":"Lineage plasticity, a cell's capacity to switch lineage-restricted gene expression states, is required for normal tissue homeostasis. Cancer lineage plasticity is increasingly observed as a mechanism of resistance to therapy, particularly molecularly targeted therapies. These therapies often owe their superior efficacy to the lineage-restricted nature of their therapeutic target, so cancers can evade such therapies by changing lineage states. As increasingly effective molecularly targeted therapies are deployed, cancer lineage plasticity is likely to be a growing clinical problem. Lineage plasticity reflects a nongenetic, potentially reversible transcriptional adaptation, but oncogenic genetic mutations likely drive elevated lineage plasticity that is typical of cancer cells. Here key concepts relevant to cancer lineage plasticity are presented, evidence implicating loss of the RB1 tumor-suppressor gene in driving cancer lineage plasticity is reviewed, and possible therapeutic approaches to counter cancer lineage plasticity are discussed.","PeriodicalId":501431,"journal":{"name":"Annual Review of Cancer Biology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138534865","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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