Sequential Administration of XPO1 and ATR Inhibitors Enhances Therapeutic Response in TP53-mutated Colorectal Cancer
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Le résumé fourni par la source
BACKGROUND & AIMS: Understanding the mechanisms by which tumors adapt to therapy is critical for developing effective combination therapeutic approaches to improve clinical outcomes for patients with cancer. METHODS: To identify promising and clinically actionable targets for managing colorectal cancer (CRC), we conducted a patient-centered functional genomics platform that includes approximately 200 genes and paired this with a high-throughput drug screen that includes 262 compounds in four patient-derived xenografts (PDXs) from patients with CRC. RESULTS: Both screening methods identified exportin 1 (XPO1) inhibitors as drivers of DNA damage-induced lethality in CRC. Molecular characterization of the cellular response to XPO1 inhibition uncovered an adaptive mechanism that limited the duration of response in TP53-mutated, but not in TP53-wild-type CRC models. Comprehensive proteomic and transcriptomic characterization revealed that the ATM/ATR-CHK1/2 axes were selectively engaged in TP53-mutant CRC cells upon XPO1 inhibitor treatment and that this response was required for adapting to therapy and escaping cell death. Administration of KPT-8602, an XPO1 inhibitor, followed by AZD-6738, an ATR inhibitor, resulted in dramatic antitumor effects and prolonged survival in TP53-mutant models of CRC. CONCLUSIONS: Our findings anticipate tremendous therapeutic benefit and support the further evaluation of XPO1 inhibitors, especially in combination with DNA damage checkpoint inhibitors, to elicit an enduring clinical response in patients with CRC harboring TP53 mutations.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- Sequential Administration of XPO1 and ATR Inhibitors Enhances Therapeutic Response in TP53-mutated Colorectal Cancer
- Date Crossref
- 01/07/2021
- Éditeur
- Elsevier BV
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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The University of Texas MD Anderson Cancer Center Department of Genomic Medicine pays non établi dans la noticeÉtablissement de santé
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Osaka Prefectural Medical Center pays non établi dans la noticeÉtablissement de santé
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Osaka City General Hospital pays non établi dans la noticeÉtablissement de santé
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The University of Osaka pays non établi dans la noticeUniversité ou école supérieure
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Texas A&M University Institute of Biosciences and Technology pays non établi dans la noticeUniversité ou école supérieure
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Osaka General Medical Center Department of Gastroenterological Surgery pays non établi dans la noticeÉtablissement de santé
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Graduate School of Medicine Department of Gastroenterology and Hepatology pays non établi dans la noticeUniversité ou école supérieure
Department of Genomic Medicine — The University of Texas MD Anderson Cancer Center, Osaka Prefectural Medical Center et Osaka City General Hospital, avec 4 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.