Laura Urbach, Lena Wieland, Frederike Penz, Rebecca Diya Samuel, Stefan Küffer, Lukas Klein, Christof Lenz, Ulrich Sax, Michael Ghadimi, Ramona Schulz-Heddergott, Elisabeth Hessmann, Volker Ellenrieder, Nelson Dusetti, Shiv K. Singh
{"title":"TP53 missense–specific transcriptional plasticity drives resistance against cell cycle inhibitors in pancreatic cancer","authors":"Laura Urbach, Lena Wieland, Frederike Penz, Rebecca Diya Samuel, Stefan Küffer, Lukas Klein, Christof Lenz, Ulrich Sax, Michael Ghadimi, Ramona Schulz-Heddergott, Elisabeth Hessmann, Volker Ellenrieder, Nelson Dusetti, Shiv K. Singh","doi":"10.1126/sciadv.adu2339","DOIUrl":null,"url":null,"abstract":"<div >In ~70% of patients with pancreatic ductal adenocarcinoma, the <i>TP53</i> gene acquires gain-of-function (GOF) mutations leading to rapid disease progression. Specifically, missense p53 (misp53) GOF mutations associate with therapy resistance and worse clinical outcomes. However, the molecular functions of distinct misp53 mutants in plasticity and therapy response remain unclear. Integrating multicenter patient data and multi-omics, we report that the misp53<sup>R273H/C</sup> mutant is associated with cell cycle progression and a basal-like state compared to the misp53<sup>R248W/Q</sup> mutant. Loss of misp53<sup>R273H/C</sup> decreased tumor growth and liver metastasis while prolonging survival in preclinical models. We found that misp53<sup>R273H/C</sup> specifically regulated the Rb/DREAM axis involved in cell cycle regulation. Notably, a clinical CDK4/6 inhibitor reduced misp53<sup>R273H/C</sup> mutant expression. However, it triggered MAPK/ERK-mediated resistance mechanisms, enhancing cell survival and resistance to CDK4/6 inhibitors. Combining MAPK/ERK and CDK4/6 inhibitors reduced misp53<sup>R273H/C</sup>-associated oncogenic functions. Thus, distinct misp53 mutants show unique cell-intrinsic plasticity, therapeutic vulnerabilities, and resistance mechanisms.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"11 27","pages":""},"PeriodicalIF":11.7000,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.adu2339","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Science Advances","FirstCategoryId":"103","ListUrlMain":"https://www.science.org/doi/10.1126/sciadv.adu2339","RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MULTIDISCIPLINARY SCIENCES","Score":null,"Total":0}
引用次数: 0
Abstract
In ~70% of patients with pancreatic ductal adenocarcinoma, the TP53 gene acquires gain-of-function (GOF) mutations leading to rapid disease progression. Specifically, missense p53 (misp53) GOF mutations associate with therapy resistance and worse clinical outcomes. However, the molecular functions of distinct misp53 mutants in plasticity and therapy response remain unclear. Integrating multicenter patient data and multi-omics, we report that the misp53R273H/C mutant is associated with cell cycle progression and a basal-like state compared to the misp53R248W/Q mutant. Loss of misp53R273H/C decreased tumor growth and liver metastasis while prolonging survival in preclinical models. We found that misp53R273H/C specifically regulated the Rb/DREAM axis involved in cell cycle regulation. Notably, a clinical CDK4/6 inhibitor reduced misp53R273H/C mutant expression. However, it triggered MAPK/ERK-mediated resistance mechanisms, enhancing cell survival and resistance to CDK4/6 inhibitors. Combining MAPK/ERK and CDK4/6 inhibitors reduced misp53R273H/C-associated oncogenic functions. Thus, distinct misp53 mutants show unique cell-intrinsic plasticity, therapeutic vulnerabilities, and resistance mechanisms.
期刊介绍:
Science Advances, an open-access journal by AAAS, publishes impactful research in diverse scientific areas. It aims for fair, fast, and expert peer review, providing freely accessible research to readers. Led by distinguished scientists, the journal supports AAAS's mission by extending Science magazine's capacity to identify and promote significant advances. Evolving digital publishing technologies play a crucial role in advancing AAAS's global mission for science communication and benefitting humankind.