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Epitranscriptomics & Cancer Adaptation : A.David

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Our research work focuses on the contribution of post-transcriptional mechanisms on cancer cell adaptation, in particular RNA epigenetic & translational control.

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Group name EquipeCTCS
Item Type Journal Article
Title CDK inhibition results in pharmacologic BRCAness increasing sensitivity to olaparib in BRCA1-WT and olaparib resistant in Triple Negative Breast Cancer
Creator Orhan et al.
Author Esin Orhan
Author Carolina Velazquez
Author Imene Tabet
Author Lise Fenou
Author Geneviève Rodier
Author Béatrice Orsetti
Author William Jacot
Author Claude Sardet
Author Charles Theillet
Abstract One in three Triple Negative Breast Cancer (TNBC) is Homologous Recombination Deficient (HRD) and susceptible to respond to PARP inhibitor (PARPi), however, resistance resulting from functional HR restoration is frequent. Thus, pharmacologic approaches that induce HRD are of interest. We investigated the effectiveness of CDK-inhibition to induce HRD and increase PARPi sensitivity of TNBC cell lines and PDX models. Two CDK-inhibitors (CDKi), the broad range dinaciclib and the CDK12-specific SR-4835, strongly reduced the expression of key HR genes and impaired HR functionality, as illustrated by BRCA1 and RAD51 nuclear foci obliteration. Consequently, both CDKis showed synergism with olaparib, as well as with cisplatin and gemcitabine, in a range of TNBC cell lines and particularly in olaparib-resistant models. In vivo assays on PDX validated the efficacy of dinaciclib which increased the sensitivity to olaparib of 5/6 models, including two olaparib-resistant and one BRCA1-WT model. However, no olaparib response improvement was observed in vivo with SR-4835. These data support that the implementation of CDK-inhibitors could be effective to sensitize TNBC to olaparib as well as possibly to cisplatin or gemcitabine.
Publication Cancer Letters
Volume 589
Pages 216820
Date 2024-05-01
Journal Abbr Cancer Lett
Language eng
DOI 10.1016/j.canlet.2024.216820
ISSN 1872-7980
Library Catalog PubMed
Extra PMID: 38574883
Tags Antineoplastic Agents, BRCA1, BRCA1 Protein, CDK9/12-Inhibitor, Cell Line, Tumor, Cisplatin, corresponding, Drug Resistance, Neoplasm, first, first-last-corresponding, HRD, Humans, last, original, Pharmacologic-BRCAness, phd, Phthalazines, Piperazines, Poly(ADP-ribose) Polymerase Inhibitors, TNBC, top, Triple Negative Breast Neoplasms
Date Added 2025/01/13 - 11:59:19
Date Modified 2025/01/16 - 11:20:13
Notes and Attachments PubMed entry (Attachment)


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