دورية أكاديمية
أعرض في EDS

Syk-dependent homologous recombination activation promotes cancer resistance to DNA targeted therapy.

التفاصيل البيبلوغرافية
العنوان: Syk-dependent homologous recombination activation promotes cancer resistance to DNA targeted therapy.
المؤلفون: Zhou Q; Department of Radiation Oncology, Mayo Clinic, Rochester, MN 55905, United States., Tu X; Department of Radiation Oncology, Mayo Clinic, Rochester, MN 55905, United States., Hou X; Department of Oncology, Mayo Clinic, Rochester, MN 55905, United States., Yu J; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, United States., Zhao F; Department of Oncology, Mayo Clinic, Rochester, MN 55905, United States., Huang J; Department of Oncology, Mayo Clinic, Rochester, MN 55905, United States., Kloeber J; Department of Oncology, Mayo Clinic, Rochester, MN 55905, United States., Olson A; Department of Radiation Oncology, Mayo Clinic, Rochester, MN 55905, United States., Gao M; Department of Oncology, Mayo Clinic, Rochester, MN 55905, United States., Luo K; Department of Oncology, Mayo Clinic, Rochester, MN 55905, United States., Zhu S; Department of Oncology, Mayo Clinic, Rochester, MN 55905, United States., Wu Z; Department of Oncology, Mayo Clinic, Rochester, MN 55905, United States., Zhang Y; Department of Oncology, Mayo Clinic, Rochester, MN 55905, United States., Sun C; AMITA Health Saint Joseph Hospital Chicago, Chicago, IL 60657, United States., Zeng X; Department of Oncology, Mayo Clinic, Rochester, MN 55905, United States., Schoolmeester KJ; Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, United States., Weroha JS; Department of Oncology, Mayo Clinic, Rochester, MN 55905, United States., Hu X; Nursing Department, Rochester Community and Technical College, Rochester, MN 55904, United States., Jiang Y; Department of Radiation Oncology, Mayo Clinic, Rochester, MN 55905, United States., Wang L; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, United States., Mutter RW; Department of Radiation Oncology, Mayo Clinic, Rochester, MN 55905, United States; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, United States. Electronic address: mutter.robert@mayo.edu., Lou Z; Department of Oncology, Mayo Clinic, Rochester, MN 55905, United States; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, United States. Electronic address: lou.zhenkun@mayo.edu.
المصدر: Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy [Drug Resist Updat] 2024 May; Vol. 74, pp. 101085. Date of Electronic Publication: 2024 Apr 16.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't; Research Support, N.I.H., Extramural
اللغة: English
بيانات الدورية: Publisher: Churchill Livingstone Country of Publication: Scotland NLM ID: 9815369 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1532-2084 (Electronic) Linking ISSN: 13687646 NLM ISO Abbreviation: Drug Resist Updat Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Edinburgh ; Philadelphia : Churchill Livingstone, c1998-
مواضيع طبية MeSH: Syk Kinase*/metabolism , Syk Kinase*/genetics , Syk Kinase*/antagonists & inhibitors , Homologous Recombination* , DNA Breaks, Double-Stranded*/drug effects , Drug Resistance, Neoplasm*/genetics , Drug Resistance, Neoplasm*/drug effects, Humans ; Female ; Phosphorylation ; Poly(ADP-ribose) Polymerase Inhibitors/pharmacology ; Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use ; Ovarian Neoplasms/drug therapy ; Ovarian Neoplasms/genetics ; Ovarian Neoplasms/pathology ; DNA Repair/drug effects ; Ataxia Telangiectasia Mutated Proteins/metabolism ; Ataxia Telangiectasia Mutated Proteins/antagonists & inhibitors ; Ataxia Telangiectasia Mutated Proteins/genetics ; Triple Negative Breast Neoplasms/genetics ; Triple Negative Breast Neoplasms/drug therapy ; Triple Negative Breast Neoplasms/pathology ; Animals ; Cell Line, Tumor ; DNA Damage/drug effects
مستخلص: Enhanced DNA repair is an important mechanism of inherent and acquired resistance to DNA targeted therapies, including poly ADP ribose polymerase (PARP) inhibition. Spleen associated tyrosine kinase (Syk) is a non-receptor tyrosine kinase acknowledged for its regulatory roles in immune cell function, cell adhesion, and vascular development. This study presents evidence indicating that Syk expression in high-grade serous ovarian cancer and triple-negative breast cancers promotes DNA double-strand break resection, homologous recombination (HR), and subsequent therapeutic resistance. Our investigations reveal that Syk is activated by ATM following DNA damage and is recruited to DNA double-strand breaks by NBS1. Once localized to the break site, Syk phosphorylates CtIP, a pivotal mediator of resection and HR, at Thr-847 to promote repair activity, particularly in Syk-expressing cancer cells. Inhibition of Syk or its genetic deletion impedes CtIP Thr-847 phosphorylation and overcomes the resistant phenotype. Collectively, our findings suggest a model wherein Syk fosters therapeutic resistance by promoting DNA resection and HR through a hitherto uncharacterized ATM-Syk-CtIP pathway. Moreover, Syk emerges as a promising tumor-specific target to sensitize Syk-expressing tumors to PARP inhibitors, radiation and other DNA-targeted therapies.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier Ltd. All rights reserved.)
التعليقات: Update of: Res Sq. 2023 Jun 09;:. (PMID: 37333340)
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معلومات مُعتمدة: K12 HD065987 United States HD NICHD NIH HHS; P50 CA116201 United States CA NCI NIH HHS; R01 CA264600 United States CA NCI NIH HHS; P30 CA015083 United States CA NCI NIH HHS; P50 CA136393 United States CA NCI NIH HHS
فهرسة مساهمة: Keywords: Cancer resistance; CtIP; DNA targeted therapy; Homologous recombination; Syk
المشرفين على المادة: EC 2.7.10.2 (Syk Kinase)
EC 2.7.10.2 (SYK protein, human)
0 (Poly(ADP-ribose) Polymerase Inhibitors)
EC 2.7.11.1 (Ataxia Telangiectasia Mutated Proteins)
تواريخ الأحداث: Date Created: 20240418 Date Completed: 20240505 Latest Revision: 20240529
رمز التحديث: 20240529
مُعرف محوري في PubMed: PMC11095636
DOI: 10.1016/j.drup.2024.101085
PMID: 38636338
قاعدة البيانات: MEDLINE
الوصف
تدمد:1532-2084
DOI:10.1016/j.drup.2024.101085