دورية أكاديمية
أعرض في EDS

Deoxycytidine kinase (dCK) inhibition is synthetic lethal with BRCA2 deficiency.

التفاصيل البيبلوغرافية
العنوان: Deoxycytidine kinase (dCK) inhibition is synthetic lethal with BRCA2 deficiency.
المؤلفون: Guantay L; Centro de Investigaciones en Bioquímica Clínica e Inmunología, CIBICI-CONICET, Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina., Garro C; OncoPrecision, New York, NY, United States., Siri S; Fundación Instituto Leloir - CONICET, Buenos Aires, Argentina., Pansa MF; Centro de Investigaciones en Bioquímica Clínica e Inmunología, CIBICI-CONICET, Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina; GlaxoSmithKline, Global Health R&D, Upper Providence, PA, United States., Ghidelli-Disse S; Cellzome GmbH - a GSK Company, 69117 Heidelberg, Germany., Paviolo N; Fundación Instituto Leloir - CONICET, Buenos Aires, Argentina., Racca A; Centro de Investigaciones en Bioquímica Clínica e Inmunología, CIBICI-CONICET, Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina., Nicotra V; Facultad de Ciencias Químicas, Instituto Multidisciplinario de Biología Vegetal (IMBIV-CONICET), Universidad Nacional de Córdoba, Córdoba, Argentina., Radu C; University of California, Los Angeles, CA, United States., Bocco JL; Centro de Investigaciones en Bioquímica Clínica e Inmunología, CIBICI-CONICET, Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina., Felice R; GlaxoSmithKline, Southern Cone LatAm, Buenos Aires, Argentina., Jansson KH; GlaxoSmithKline, Global Health R&D, Upper Providence, PA, United States., Remlinger K; GlaxoSmithKline, Global Health R&D, Upper Providence, PA, United States., Amador A; GlaxoSmithKline, Global Health R&D, Upper Providence, PA, United States., Stronach E; GlaxoSmithKline, Global Health R&D, Stevenage, United Kingdom., Coleman K; GlaxoSmithKline, Synthetic Lethal RU, Waltham, MA, United States., Muelbaier M; Cellzome GmbH - a GSK Company, 69117 Heidelberg, Germany., Drewes G; Cellzome GmbH - a GSK Company, 69117 Heidelberg, Germany., Gloger I; GlaxoSmithKline, Global Health R&D, Stevenage, United Kingdom., Madauss K; GlaxoSmithKline, Global Health R&D, Upper Providence, PA, United States., García M; Facultad de Ciencias Químicas, Instituto Multidisciplinario de Biología Vegetal (IMBIV-CONICET), Universidad Nacional de Córdoba, Córdoba, Argentina., Gottifredi V; Fundación Instituto Leloir - CONICET, Buenos Aires, Argentina., Soria G; OncoPrecision, New York, NY, United States. Electronic address: gaston@oncoprecision.bio.
المصدر: Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy [Drug Resist Updat] 2023 Mar; Vol. 67, pp. 100932. Date of Electronic Publication: 2023 Jan 22.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
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: Deoxycytidine Kinase*/genetics , Deoxycytidine Kinase*/metabolism , Antineoplastic Agents*/pharmacology , Antineoplastic Agents*/therapeutic use, Humans ; Poly(ADP-ribose) Polymerase Inhibitors ; Nucleotides/metabolism ; Protein Kinase Inhibitors/pharmacology ; Protein Kinase Inhibitors/therapeutic use ; BRCA2 Protein/genetics
مستخلص: BRCA2 is a well-established cancer driver in several human malignancies. While the remarkable success of PARP inhibitors proved the clinical potential of targeting BRCA deficiencies, the emergence of resistance mechanisms underscores the importance of seeking novel Synthetic Lethal (SL) targets for future drug development efforts. In this work, we performed a BRCA2-centric SL screen with a collection of plant-derived compounds from South America. We identified the steroidal alkaloid Solanocapsine as a selective SL inducer, and we were able to substantially increase its potency by deriving multiple analogs. The use of two complementary chemoproteomic approaches led to the identification of the nucleotide salvage pathway enzyme deoxycytidine kinase (dCK) as Solanocapsine's target responsible for its BRCA2-linked SL induction. Additional confirmatory evidence was obtained by using the highly specific dCK inhibitor (DI-87), which induces SL in multiple BRCA2-deficient and KO contexts. Interestingly, dCK-induced SL is mechanistically different from the one induced by PARP inhibitors. dCK inhibition generates substantially lower levels of DNA damage, and cytotoxic phenotypes are associated exclusively with mitosis, thus suggesting that the fine-tuning of nucleotide supply in mitosis is critical for the survival of BRCA2-deficient cells. Moreover, by using a xenograft model of contralateral tumors, we show that dCK impairment suffices to trigger SL in-vivo. Taken together, our findings unveil dCK as a promising new target for BRCA2-deficient cancers, thus setting the ground for future therapeutic alternatives to PARP inhibitors.
(Copyright © 2023 Elsevier Ltd. All rights reserved.)
فهرسة مساهمة: Keywords: PARP inhibitors BRCA2 Nucleotides metabolism Synthetic Lethality Targeted Therapies
المشرفين على المادة: EC 2.7.1.74 (Deoxycytidine Kinase)
0 (Poly(ADP-ribose) Polymerase Inhibitors)
0 (Antineoplastic Agents)
0 (Nucleotides)
0 (Protein Kinase Inhibitors)
0 (BRCA2 protein, human)
0 (BRCA2 Protein)
تواريخ الأحداث: Date Created: 20230127 Date Completed: 20230223 Latest Revision: 20231214
رمز التحديث: 20231215
DOI: 10.1016/j.drup.2023.100932
PMID: 36706533
قاعدة البيانات: MEDLINE
الوصف
تدمد:1532-2084
DOI:10.1016/j.drup.2023.100932