TP53 missense–specific transcriptional plasticity drives resistance against cell cycle inhibitors in pancreatic cancer

IF 11.7 1区 综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES
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
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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.

Abstract Image

胰腺癌中TP53错义特异性转录可塑性驱动对细胞周期抑制剂的抗性
在约70%的胰腺导管腺癌患者中,TP53基因获得功能获得(GOF)突变导致疾病快速进展。具体来说,错义p53 (misp53) GOF突变与治疗耐药和更差的临床结果相关。然而,不同的p53突变体在可塑性和治疗反应中的分子功能尚不清楚。整合多中心患者数据和多组学,我们报告misp53R273H/C突变与misp53R248W/Q突变相比,misp53R273H/C突变与细胞周期进展和基底样状态相关。在临床前模型中,缺失misp53R273H/C可降低肿瘤生长和肝转移,同时延长生存期。我们发现misp53R273H/C特异性调控参与细胞周期调控的Rb/DREAM轴。值得注意的是,临床CDK4/6抑制剂降低了misp53R273H/C突变体的表达。然而,它触发了MAPK/ erk介导的耐药机制,增强了细胞存活和对CDK4/6抑制剂的耐药性。结合MAPK/ERK和CDK4/6抑制剂可降低misp53R273H/ c相关的致癌功能。因此,不同的p53突变体表现出独特的细胞内在可塑性、治疗脆弱性和抗性机制。
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来源期刊
Science Advances
Science Advances 综合性期刊-综合性期刊
CiteScore
21.40
自引率
1.50%
发文量
1937
审稿时长
29 weeks
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.
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