Matthias Hinterndorfer, Valentina A. Spiteri, Alessio Ciulli, Georg E. Winter
{"title":"Targeted protein degradation for cancer therapy","authors":"Matthias Hinterndorfer, Valentina A. Spiteri, Alessio Ciulli, Georg E. Winter","doi":"10.1038/s41568-025-00817-8","DOIUrl":"https://doi.org/10.1038/s41568-025-00817-8","url":null,"abstract":"<p>Targeted protein degradation (TPD) aims at reprogramming the target specificity of the ubiquitin–proteasome system, the major cellular protein disposal machinery, to induce selective ubiquitination and degradation of therapeutically relevant proteins. Since its conception over 20 years ago, TPD has gained a lot of attention mainly due to improvements in the design of bifunctional proteolysis targeting chimeras (PROTACs) and understanding the mechanisms underlying molecular glue degraders. Today, PROTACs are on the verge of a first clinical approval and recent structural and mechanistic insights combined with technological leaps promise to unlock the rational design of protein degraders, following the lead of lenalidomide and related clinically approved analogues. At the same time, the TPD universe is expanding at a record speed with the discovery of novel modalities beyond molecular glue degraders and PROTACs. Here we review the recent progress in the field, focusing on newly discovered degrader modalities, the current state of clinical degrader candidates for cancer therapy and upcoming design approaches.</p>","PeriodicalId":19055,"journal":{"name":"Nature Reviews Cancer","volume":"91 1","pages":""},"PeriodicalIF":78.5,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143875881","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Androgen receptor activation for breast cancer therapy","authors":"Dimple Notani","doi":"10.1038/s41568-025-00821-y","DOIUrl":"https://doi.org/10.1038/s41568-025-00821-y","url":null,"abstract":"In this Journal Club, Dimple Notani discusses a study that demonstrates a tumour suppressive function of the androgen receptor in oestrogen receptor-positive breast cancer.","PeriodicalId":19055,"journal":{"name":"Nature Reviews Cancer","volume":"529 1","pages":""},"PeriodicalIF":78.5,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143866328","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Measuring HLA disruption using MHC Hammer","authors":"Clare Puttick","doi":"10.1038/s41568-025-00822-x","DOIUrl":"https://doi.org/10.1038/s41568-025-00822-x","url":null,"abstract":"In this Tools of the Trade article, Clare Puttick describes the development of MHC Hammer, a computational tool that uses whole-exome sequencing and RNA sequencing data for measuring HLA disruption.","PeriodicalId":19055,"journal":{"name":"Nature Reviews Cancer","volume":"232 1","pages":""},"PeriodicalIF":78.5,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143862199","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Evolutionary paths towards metastasis","authors":"Kamila Naxerova","doi":"10.1038/s41568-025-00814-x","DOIUrl":"https://doi.org/10.1038/s41568-025-00814-x","url":null,"abstract":"<p>The evolution of metastasis in humans is considerably less well understood than the biology of early carcinogenesis. For over a century, clinicians and scientists have been debating whether metastatic potential is the intrinsic property of a cancer, pre-determined by the molecular characteristics of the tumour founder cell, or whether metastatic capacity evolves in a stepwise fashion as the tumour grows, akin to the multistage accumulation of oncogenic alterations that give rise to the first cancer cell. In this Perspective, I examine how genetic analyses of primary tumours and matched metastases can distinguish between these two competing metastasis evolution models, with particular emphasis on the utility of metastatic randomness — a quantitative measure that reflects whether metastases arise from a random selection of primary tumour subclones or whether they are enriched for descendants of privileged lineages that have acquired pro-metastatic traits. Probable metastasis evolution trajectories in tumours with high and low baseline metastatic capacity are discussed, along with the role of seeding rates and selection at different metastatic host sites. Finally, I argue that trailblazing insights into human metastasis biology are immediately possible if we make a concerted effort to apply existing experimental and theoretical tools to the right patient cohorts.</p>","PeriodicalId":19055,"journal":{"name":"Nature Reviews Cancer","volume":"43 1","pages":""},"PeriodicalIF":78.5,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143857775","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"CRISPR-StAR to transform in vivo functional genomic screening","authors":"Christopher Lowden","doi":"10.1038/s41568-025-00818-7","DOIUrl":"https://doi.org/10.1038/s41568-025-00818-7","url":null,"abstract":"In this Tools of the Trade article, Christopher Lowden describes the development and use of CRISPR-StAR, which leverages internal controls to overcome experimental noise for improved in vivo functional genomic screens.","PeriodicalId":19055,"journal":{"name":"Nature Reviews Cancer","volume":"115 1","pages":""},"PeriodicalIF":78.5,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143836642","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Kathryn L. Simpson, Dominic G. Rothwell, Fiona Blackhall, Caroline Dive
{"title":"Challenges of small cell lung cancer heterogeneity and phenotypic plasticity","authors":"Kathryn L. Simpson, Dominic G. Rothwell, Fiona Blackhall, Caroline Dive","doi":"10.1038/s41568-025-00803-0","DOIUrl":"https://doi.org/10.1038/s41568-025-00803-0","url":null,"abstract":"<p>Small cell lung cancer (SCLC) is an aggressive neuroendocrine malignancy with ~7% 5-year overall survival reflecting early metastasis and rapid acquired chemoresistance. Immunotherapy briefly extends overall survival in ~15% cases, yet predictive biomarkers are lacking. Targeted therapies are beginning to show promise, with a recently approved delta-like ligand 3 (DLL3)-targeted therapy impacting the treatment landscape. The increased availability of patient-faithful models, accumulating human tumour biobanks and numerous comprehensive molecular profiling studies have collectively facilitated the mapping and understanding of substantial intertumoural and intratumoural heterogeneity. Beyond the almost ubiquitous loss of wild-type p53 and RB1, SCLC is characterized by heterogeneously mis-regulated expression of MYC family members, yes-associated protein 1 (YAP1), NOTCH pathway signalling, anti-apoptotic BCL2 and epigenetic regulators. Molecular subtypes are based on the neurogenic transcription factors achaete-scute homologue 1 (ASCL1) and neurogenic differentiation factor 1 (NEUROD1), the rarer non-neuroendocrine transcription factor POU class 2 homeobox 3 (POU2F3), and immune- and inflammation-related signatures. Furthermore, SCLC shows phenotypic plasticity, including neuroendocrine-to-non-neuroendocrine transition driven by NOTCH signalling, which is associated with disease progression, chemoresistance and immune modulation and, in mouse models, with metastasis. Although these features pose substantial challenges, understanding the molecular vulnerabilities of transcription factor subtypes, the functional relevance of plasticity and cell cooperation offer opportunities for personalized therapies informed by liquid and tissue biomarkers.</p>","PeriodicalId":19055,"journal":{"name":"Nature Reviews Cancer","volume":"8 1","pages":""},"PeriodicalIF":78.5,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143813620","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"TurboCas for locus-specific proximity labelling","authors":"Bercin Cenik","doi":"10.1038/s41568-025-00815-w","DOIUrl":"https://doi.org/10.1038/s41568-025-00815-w","url":null,"abstract":"In this Tools of the Trade article, Bercin Cenik describes the development and use of TurboCas, an enzyme that pairs catalytically dead Cas9 with the proximity-labelling enzyme miniTurbo to map the regulatory proteins that shape transcription.","PeriodicalId":19055,"journal":{"name":"Nature Reviews Cancer","volume":"1 1","pages":""},"PeriodicalIF":78.5,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143805930","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Blocking cholesterol biosynthesis to clean out cancer","authors":"Daniela Senft","doi":"10.1038/s41568-025-00816-9","DOIUrl":"https://doi.org/10.1038/s41568-025-00816-9","url":null,"abstract":"The mechanisms of how pH-dependent cell death, alkaliptosis, is regulated are incompletely understood. Chen et al. now demonstrate that the cholesterol biosynthesis protein CYP51A1 suppresses alkaliptosis induced by the opioid analgesic JTC801.","PeriodicalId":19055,"journal":{"name":"Nature Reviews Cancer","volume":"24 1","pages":""},"PeriodicalIF":78.5,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143775658","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Alicia Llorente, Gurpreet K. Arora, Rabi Murad, Brooke M. Emerling
{"title":"Phosphoinositide kinases in cancer: from molecular mechanisms to therapeutic opportunities","authors":"Alicia Llorente, Gurpreet K. Arora, Rabi Murad, Brooke M. Emerling","doi":"10.1038/s41568-025-00810-1","DOIUrl":"https://doi.org/10.1038/s41568-025-00810-1","url":null,"abstract":"<p>Phosphoinositide kinases, extending beyond the well-known phosphoinositide 3-kinase (PI3K), are key players in the dynamic and site-specific phosphorylation of lipid phosphoinositides. Unlike PI3Ks, phosphatidylinositol 4-kinases (PI4Ks) and phosphatidylinositol phosphate kinases (PIPKs) do not usually exhibit mutational alterations, but mostly show altered expression in tumours, orchestrating a broad spectrum of signalling, metabolic and immune processes, all of which are crucial in the pathogenesis of cancer. Dysregulation of PI4Ks and PIPKs has been associated with various malignancies, which has sparked considerable interest towards their therapeutic targeting. In this Review we summarize the current understanding of the lesser-studied phosphoinositide kinase families, PI4K and PIPK, focusing on their functions and relevance in cancer. In addition, we provide an overview of ongoing efforts driving the preclinical and clinical development of phosphoinositide kinase-targeting molecules.</p>","PeriodicalId":19055,"journal":{"name":"Nature Reviews Cancer","volume":"32 1","pages":""},"PeriodicalIF":78.5,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143766564","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Dong Guo, Ying Meng, Gaoxiang Zhao, Qingang Wu, Zhimin Lu
{"title":"Moonlighting functions of glucose metabolic enzymes and metabolites in cancer","authors":"Dong Guo, Ying Meng, Gaoxiang Zhao, Qingang Wu, Zhimin Lu","doi":"10.1038/s41568-025-00800-3","DOIUrl":"https://doi.org/10.1038/s41568-025-00800-3","url":null,"abstract":"<p>Glucose metabolic enzymes and their metabolites not only provide energy and building blocks for synthesizing macromolecules but also possess non-canonical or moonlighting functions in response to extracellular and intracellular signalling. These moonlighting functions modulate various cellular activities, including gene expression, cell cycle progression, DNA repair, autophagy, senescence and apoptosis, cell proliferation, remodelling of the tumour microenvironment and immune responses. These functions integrate glucose metabolism with other essential cellular activities, driving cancer progression. Targeting these moonlighting functions could open new therapeutic avenues and lead to cancer-specific treatments.</p>","PeriodicalId":19055,"journal":{"name":"Nature Reviews Cancer","volume":"38 1","pages":""},"PeriodicalIF":78.5,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143758516","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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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