The molecular and functional landscape of resistance to FOLFIRI chemotherapy in metastatic colorectal cancer.

IF 33.3 1区医学 Q1 ONCOLOGY

Cancer discovery Pub Date : 2025-09-22 DOI:10.1158/2159-8290.cd-24-0556

Marco Avolio,Simonetta M Leto,Francesco Sassi,Barbara Lupo,Elena Grassi,Irene Catalano,Eugenia R Zanella,Valentina Vurchio,Francesca Cottino,Petros K Tsantoulis,Luca Lazzari,Paolo Luraghi,Martina Ferri,Francesco Galimi,Enrico Berrino,Sara E Bellomo,Marco Viviani,Alberto Sogari,Gianluca Mauri,Federica Tosi,Federica Cruciani,Andrea Sartore-Bianchi,Salvatore Siena,Felice Borghi,Valter Torri,Elena Élez,Josep Tabernero,Maria Nieva,Clara Montagut,Noelia Tarazona,Andres Cervantes,Sabine Tejpar,Alberto Bardelli,Caterina Marchiò,Silvia Marsoni,Andrea Bertotti,Livio Trusolino

{"title":"The molecular and functional landscape of resistance to FOLFIRI chemotherapy in metastatic colorectal cancer.","authors":"Marco Avolio,Simonetta M Leto,Francesco Sassi,Barbara Lupo,Elena Grassi,Irene Catalano,Eugenia R Zanella,Valentina Vurchio,Francesca Cottino,Petros K Tsantoulis,Luca Lazzari,Paolo Luraghi,Martina Ferri,Francesco Galimi,Enrico Berrino,Sara E Bellomo,Marco Viviani,Alberto Sogari,Gianluca Mauri,Federica Tosi,Federica Cruciani,Andrea Sartore-Bianchi,Salvatore Siena,Felice Borghi,Valter Torri,Elena Élez,Josep Tabernero,Maria Nieva,Clara Montagut,Noelia Tarazona,Andres Cervantes,Sabine Tejpar,Alberto Bardelli,Caterina Marchiò,Silvia Marsoni,Andrea Bertotti,Livio Trusolino","doi":"10.1158/2159-8290.cd-24-0556","DOIUrl":null,"url":null,"abstract":"The combination of 5-fluorouracil and irinotecan (FOLFIRI) remains a standard-of-care treatment for metastatic colorectal cancer (mCRC), yet benefits only about half of patients. Using patient-derived xenografts (PDXs), we investigated the biological underpinnings of this heterogeneous response. FOLFIRI-resistant models showed transcriptional upregulation of innate immunity and mitochondrial metabolism genes, together with reduced expression of the DNA polymerase POLD1. Sensitive counterparts exhibited a BRCAness-like phenotype with genomic scars of homologous recombination (HR) deficiency, not caused by genetic or epigenetic loss of HR genes but by low abundance of the RAD51 recombinase. In tumoroids, forced RAD51 overexpression attenuated HR deficiency-related scars and chemotherapy-induced damage, while HR inhibition through ATM blockade enhanced drug sensitivity. The predictive relevance of key response determinants was validated in clinical samples. This work illuminates functional, non-genetic facets of BRCAness in mCRC and introduces actionable biomarkers and targets, offering prospects to improve clinical decision-making and broaden therapeutic options for chemorefractory patients.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"50 1","pages":""},"PeriodicalIF":33.3000,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cancer discovery","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1158/2159-8290.cd-24-0556","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

The combination of 5-fluorouracil and irinotecan (FOLFIRI) remains a standard-of-care treatment for metastatic colorectal cancer (mCRC), yet benefits only about half of patients. Using patient-derived xenografts (PDXs), we investigated the biological underpinnings of this heterogeneous response. FOLFIRI-resistant models showed transcriptional upregulation of innate immunity and mitochondrial metabolism genes, together with reduced expression of the DNA polymerase POLD1. Sensitive counterparts exhibited a BRCAness-like phenotype with genomic scars of homologous recombination (HR) deficiency, not caused by genetic or epigenetic loss of HR genes but by low abundance of the RAD51 recombinase. In tumoroids, forced RAD51 overexpression attenuated HR deficiency-related scars and chemotherapy-induced damage, while HR inhibition through ATM blockade enhanced drug sensitivity. The predictive relevance of key response determinants was validated in clinical samples. This work illuminates functional, non-genetic facets of BRCAness in mCRC and introduces actionable biomarkers and targets, offering prospects to improve clinical decision-making and broaden therapeutic options for chemorefractory patients.

查看原文本刊更多论文

转移性结直肠癌对FOLFIRI化疗耐药的分子和功能景观。

5-氟尿嘧啶联合伊立替康（FOLFIRI）仍然是转移性结直肠癌（mCRC）的标准治疗方法，但只有大约一半的患者受益。使用患者来源的异种移植物（PDXs），我们研究了这种异质反应的生物学基础。folfiri耐药模型显示先天免疫和线粒体代谢基因转录上调，同时DNA聚合酶POLD1表达降低。敏感的对应物表现出brcaness样表型，具有同源重组（HR）缺陷的基因组疤痕，这不是由HR基因的遗传或表观遗传损失引起的，而是由低丰度的RAD51重组酶引起的。在类肿瘤中，强迫RAD51过表达减轻了HR缺陷相关的疤痕和化疗引起的损伤，而通过ATM阻断HR抑制增强了药物敏感性。关键反应决定因素的预测相关性在临床样本中得到验证。这项工作阐明了mCRC中BRCAness的功能，非遗传方面，并介绍了可操作的生物标志物和靶点，为改善临床决策和拓宽化疗难治患者的治疗选择提供了前景。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Cancer discovery ONCOLOGY-

CiteScore

22.90

自引率

1.40%

发文量

838

审稿时长

6-12 weeks

期刊介绍： Cancer Discovery publishes high-impact, peer-reviewed articles detailing significant advances in both research and clinical trials. Serving as a premier cancer information resource, the journal also features Review Articles, Perspectives, Commentaries, News stories, and Research Watch summaries to keep readers abreast of the latest findings in the field. Covering a wide range of topics, from laboratory research to clinical trials and epidemiologic studies, Cancer Discovery spans the entire spectrum of cancer research and medicine.