دورية أكاديمية
Activity of the Ubiquitin-activating Enzyme Inhibitor TAK-243 in Adrenocortical Carcinoma Cell Lines, Patient-derived Organoids, and Murine Xenografts.
| العنوان: | Activity of the Ubiquitin-activating Enzyme Inhibitor TAK-243 in Adrenocortical Carcinoma Cell Lines, Patient-derived Organoids, and Murine Xenografts. |
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| المؤلفون: | Arakawa Y; Laboratory of Molecular Pharmacology and Developmental Therapeutics Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland., Jo U; Laboratory of Molecular Pharmacology and Developmental Therapeutics Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland., Kumar S; Laboratory of Molecular Pharmacology and Developmental Therapeutics Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland., Sun NY; Laboratory of Molecular Pharmacology and Developmental Therapeutics Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland., Elloumi F; Laboratory of Molecular Pharmacology and Developmental Therapeutics Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland., Thomas A; Laboratory of Molecular Pharmacology and Developmental Therapeutics Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland., Roper N; Laboratory of Molecular Pharmacology and Developmental Therapeutics Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland., Varghese DG; Laboratory of Molecular Pharmacology and Developmental Therapeutics Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland., Takebe N; Laboratory of Molecular Pharmacology and Developmental Therapeutics Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland., Zhang X; National Center for Advancing Translational Sciences, NIH, Bethesda, Maryland., Ceribelli M; National Center for Advancing Translational Sciences, NIH, Bethesda, Maryland., Holland DO; National Center for Advancing Translational Sciences, NIH, Bethesda, Maryland., Beck E; National Center for Advancing Translational Sciences, NIH, Bethesda, Maryland., Itkin Z; National Center for Advancing Translational Sciences, NIH, Bethesda, Maryland., McKnight C; National Center for Advancing Translational Sciences, NIH, Bethesda, Maryland., Wilson KM; National Center for Advancing Translational Sciences, NIH, Bethesda, Maryland., Travers J; National Center for Advancing Translational Sciences, NIH, Bethesda, Maryland., Klumpp-Thomas C; National Center for Advancing Translational Sciences, NIH, Bethesda, Maryland., Thomas CJ; National Center for Advancing Translational Sciences, NIH, Bethesda, Maryland., Hoang CD; Thoracic Surgery Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland., Hernandez JM; Surgical Oncology Program, Center for Cancer Research, NCI, NIH, Bethesda, Maryland., Del Rivero J; Laboratory of Molecular Pharmacology and Developmental Therapeutics Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland., Pommier Y; Laboratory of Molecular Pharmacology and Developmental Therapeutics Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland. |
| المصدر: | Cancer research communications [Cancer Res Commun] 2024 Mar 19; Vol. 4 (3), pp. 834-848. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Association for Cancer Research Country of Publication: United States NLM ID: 9918281580506676 Publication Model: Print Cited Medium: Internet ISSN: 2767-9764 (Electronic) Linking ISSN: 27679764 NLM ISO Abbreviation: Cancer Res Commun Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: [Philadelphia, Pennsylvania] : American Association for Cancer Research, [2021]- |
| مواضيع طبية MeSH: | Adrenocortical Carcinoma*/drug therapy , Adrenal Cortex Neoplasms*/drug therapy , Antineoplastic Agents*/pharmacology , Bridged Bicyclo Compounds, Heterocyclic* , Sulfides* , Sulfonamides* , Pyrimidines* , Pyrazoles*, Humans ; Animals ; Mice ; Mitotane ; Heterografts ; Ubiquitin-Activating Enzymes/therapeutic use ; Cell Line, Tumor ; Organoids ; Proto-Oncogene Proteins c-bcl-2/therapeutic use ; Nuclear Proteins/therapeutic use |
| مستخلص: | Current treatment options for metastatic adrenocortical carcinoma (ACC) have limited efficacy, despite the common use of mitotane and cytotoxic agents. This study aimed to identify novel therapeutic options for ACC. An extensive drug screen was conducted to identify compounds with potential activity against ACC cell lines. We further investigated the mechanism of action of the identified compound, TAK-243, its synergistic effects with current ACC therapeutics, and its efficacy in ACC models including patient-derived organoids and mouse xenografts. TAK-243, a clinical ubiquitin-activating enzyme (UAE) inhibitor, showed potent activity in ACC cell lines. TAK-243 inhibited protein ubiquitination in ACC cells, leading to the accumulation of free ubiquitin, activation of the unfolded protein response, and induction of apoptosis. TAK-243 was found to be effluxed out of cells by MDR1, a drug efflux pump, and did not require Schlafen 11 (SLFN11) expression for its activity. Combination of TAK-243 with current ACC therapies (e.g., mitotane, etoposide, cisplatin) produced synergistic or additive effects. In addition, TAK-243 was highly synergistic with BCL2 inhibitors (Navitoclax and Venetoclax) in preclinical ACC models including patient-derived organoids. The tumor suppressive effects of TAK-243 and its synergistic effects with Venetoclax were further confirmed in a mouse xenograft model. These findings provide preclinical evidence to support the initiation of a clinical trial of TAK-243 in patients with advanced-stage ACC. TAK-243 is a promising potential treatment option for ACC, either as monotherapy or in combination with existing therapies or BCL2 inhibitors. Significance: ACC is a rare endocrine cancer with poor prognosis and limited therapeutic options. We report that TAK-243 is active alone and in combination with currently used therapies and with BCL2 and mTOR inhibitors in ACC preclinical models. Our results suggest implementation of TAK-243 in clinical trials for patients with advanced and metastatic ACC. (© 2024 The Authors; Published by the American Association for Cancer Research.) |
| معلومات مُعتمدة: | Z01 BC006150 United States ImNIH Intramural NIH HHS |
| المشرفين على المادة: | N54AIC43PW (venetoclax) V9GGV0YCDI (TAK-243) 78E4J5IB5J (Mitotane) EC 6.2.1.45 (Ubiquitin-Activating Enzymes) 0 (Antineoplastic Agents) 0 (Proto-Oncogene Proteins c-bcl-2) 0 (SLFN11 protein, human) 0 (Nuclear Proteins) 0 (Bridged Bicyclo Compounds, Heterocyclic) 0 (Sulfides) 0 (Sulfonamides) 0 (Pyrimidines) 0 (Pyrazoles) |
| تواريخ الأحداث: | Date Created: 20240307 Date Completed: 20240326 Latest Revision: 20240326 |
| رمز التحديث: | 20240326 |
| مُعرف محوري في PubMed: | PMC10949913 |
| DOI: | 10.1158/2767-9764.CRC-24-0085 |
| PMID: | 38451783 |
| قاعدة البيانات: | MEDLINE |
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