| 000 | 03657 am a22003973u 4500 | ||
|---|---|---|---|
| 042 | _adc | ||
| 100 | 1 | 0 |
_aWidmer, Carmen A. _eauthor _91672 |
| 700 | 1 | 0 |
_aKlebic, Ismar _eauthor _91673 |
| 700 | 1 | 0 |
_aDomanitskaya, Natalya _eauthor _91674 |
| 700 | 1 | 0 |
_aDecollogny, Morgane _eauthor _91675 |
| 700 | 1 | 0 |
_aHowald, Denise _eauthor _91676 |
| 700 | 1 | 0 |
_aSiffert, Myriam _eauthor _91677 |
| 700 | 1 | 0 |
_aEssers, Paul _eauthor _91678 |
| 700 | 1 | 0 |
_aNowicka, Zuzanna _eauthor _91679 |
| 700 | 1 | 0 |
_aStokar-Regenscheit, Nadine _eauthor _91680 |
| 700 | 1 | 0 |
_avan de Ven, Marieke _eauthor _91681 |
| 700 | 1 | 0 |
_ade Korte-Grimmerink, Renske _eauthor _91682 |
| 700 | 1 | 0 |
_aGalván, José A. _eauthor _91683 |
| 700 | 1 | 0 |
_aPritchard, Colin E.J. _eauthor _91684 |
| 700 | 1 | 0 |
_aHuijbers, Ivo J. _eauthor _91685 |
| 700 | 1 | 0 |
_aFendler, Wojciech _eauthor _91686 |
| 700 | 1 | 0 |
_aVens, Conchita _eauthor _91687 |
| 700 | 1 | 0 |
_aRottenberg, Sven _eauthor _91688 |
| 245 | 0 | 0 | _aLoss of the Volume-regulated Anion Channel Components LRRC8A and LRRC8D Limits Platinum Drug Efficacy |
| 260 |
_bAmerican Association for Cancer Research, _c2022-10-26. |
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| 500 | _a/pmc/articles/PMC7613873/ | ||
| 500 | _a/pubmed/36467895 | ||
| 520 | _aIn 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 | _a© 2022 The Authors; Published by the American Association for Cancer Research | ||
| 540 | _ahttps://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. | ||
| 546 | _aen | ||
| 690 |
_aResearch Article _91689 |
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| 655 | 7 |
_aText _2local |
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| 786 | 0 | _nCancer Res Commun | |
| 856 | 4 | 1 |
_uhttp://dx.doi.org/10.1158/2767-9764.CRC-22-0208 _zConnect to this object online. |
| 999 |
_c1742 _d1742 |
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