JOM KITA KE POLITEKNIK

Loss of the Volume-regulated Anion Channel Components LRRC8A and LRRC8D Limits Platinum Drug Efficacy (Record no. 823)

MARC details
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Authentication code dc
100 10 - MAIN ENTRY--PERSONAL NAME
Personal name Widmer, Carmen A.
Relator term author
9 (RLIN) 1672
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Title Loss of the Volume-regulated Anion Channel Components LRRC8A and LRRC8D Limits Platinum Drug Efficacy
260 ## - PUBLICATION, DISTRIBUTION, ETC.
Name of publisher, distributor, etc. American Association for Cancer Research,
Date of publication, distribution, etc. 2022-10-26.
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General note /pmc/articles/PMC7613873/
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General note /pubmed/36467895
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Summary, etc. In recent years, platinum (Pt) drugs have been found to be especially efficient to treat patients with cancers that lack a proper DNA damage response, for example, due to dysfunctional BRCA1. Despite this knowledge, we are still missing helpful markers to predict Pt response in the clinic. We have previously shown that volume-regulated anion channels, containing the subunits LRRC8A and LRRC8D, promote the uptake of cisplatin and carboplatin in BRCA1-proficient cell lines. Here, we show that the loss of LRRC8A or LRRC8D significantly reduces the uptake of cisplatin and carboplatin in BRCA1;p53-deficient mouse mammary tumor cells. This results in reduced DNA damage and in vivo drug resistance. In contrast to Lrrc8a, the deletion of the Lrrc8d gene does not affect the viability and fertility of mice. Interestingly, Lrrc8d(−)(/)(−) mice tolerate a 2-fold cisplatin MTD. This allowed us to establish a mouse model for intensified Pt-based chemotherapy, and we found that an increased cisplatin dose eradicates BRCA1;p53-deficient tumors, whereas eradication is not possible in wild-type mice. Moreover, we show that decreased expression of LRRC8A/D in patients with head and neck squamous cell carcinoma, who are treated with a Pt-based chemoradiotherapy, leads to decreased overall survival of the patients. In particular, high cumulative cisplatin dose treatments lost their efficacy in patients with a low LRRC8A/D expression in their cancers. Our data therefore suggest that LRRC8A and LRRC8D should be included in a prospective trial to predict the success of intensified cisplatin- or carboplatin-based chemotherapy. SIGNIFICANCE: We demonstrate that lack of expression of Lrrc8a or Lrrc8d significantly reduces the uptake and efficacy of cisplatin and carboplatin in Pt-sensitive BRCA1;p53-deficient tumors. Moreover, our work provides support to confirm the LRRC8A and LRRC8D gene expression in individual tumors prior to initiation of intensive Pt-based chemotherapy.
540 ## - TERMS GOVERNING USE AND REPRODUCTION NOTE
Terms governing use and reproduction © 2022 The Authors; Published by the American Association for Cancer Research
540 ## - TERMS GOVERNING USE AND REPRODUCTION NOTE
Terms governing use and reproduction https://creativecommons.org/licenses/by/4.0/This open access article is distributed under the Creative Commons Attribution 4.0 International (CC BY 4.0) license.
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Language note en
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Topical term or geographic name as entry element Research Article
9 (RLIN) 1689
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Genre/form data or focus term Text
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Personal name Klebic, Ismar
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9 (RLIN) 1673
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Personal name Domanitskaya, Natalya
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9 (RLIN) 1674
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Personal name Decollogny, Morgane
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9 (RLIN) 1675
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Personal name Howald, Denise
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9 (RLIN) 1676
700 10 - ADDED ENTRY--PERSONAL NAME
Personal name Siffert, Myriam
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9 (RLIN) 1677
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Personal name Essers, Paul
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9 (RLIN) 1678
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Personal name Nowicka, Zuzanna
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9 (RLIN) 1679
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Personal name Stokar-Regenscheit, Nadine
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9 (RLIN) 1680
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Personal name van de Ven, Marieke
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9 (RLIN) 1681
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Personal name de Korte-Grimmerink, Renske
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9 (RLIN) 1682
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Personal name Galván, José A.
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9 (RLIN) 1683
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Personal name Pritchard, Colin E.J.
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9 (RLIN) 1684
700 10 - ADDED ENTRY--PERSONAL NAME
Personal name Huijbers, Ivo J.
Relator term author
9 (RLIN) 1685
700 10 - ADDED ENTRY--PERSONAL NAME
Personal name Fendler, Wojciech
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9 (RLIN) 1686
700 10 - ADDED ENTRY--PERSONAL NAME
Personal name Vens, Conchita
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9 (RLIN) 1687
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Personal name Rottenberg, Sven
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9 (RLIN) 1688
786 0# - DATA SOURCE ENTRY
Note Cancer Res Commun
856 41 - ELECTRONIC LOCATION AND ACCESS
Uniform Resource Identifier <a href="http://dx.doi.org/10.1158/2767-9764.CRC-22-0208">http://dx.doi.org/10.1158/2767-9764.CRC-22-0208</a>
Public note Connect to this object online.

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