Loss of the volume-regulated anion channel components LRRC8A and LRRC8D limits platinum drug efficacy.

Autor:	Widmer CA; Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, 3012 Bern, Switzerland., Klebic I; Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, 3012 Bern, Switzerland.; COMPATH, Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, 3012 Bern, Switzerland., Domanitskaya N; Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, 3012 Bern, Switzerland., Decollogny M; Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, 3012 Bern, Switzerland., Howald D; Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, 3012 Bern, Switzerland., Siffert M; Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, 3012 Bern, Switzerland., Essers P; Department of Radiation Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands., Nowicka Z; Department of Biostatistics and Translational Medicine, Medical University of Lodz, 92-215 Lodz, Poland., Stokar-Regenscheit N; Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, 3012 Bern, Switzerland., van de Ven M; Mouse Clinic for Cancer and Aging Research (MCCA), Preclinical Intervention Unit, The Netherlands Cancer Institute, 1066CX Amsterdam, The Netherlands., de Korte-Grimmerink R; Mouse Clinic for Cancer and Aging Research (MCCA), Preclinical Intervention Unit, The Netherlands Cancer Institute, 1066CX Amsterdam, The Netherlands., Galván JA; Translational Research Unit, Institute of Pathology, University of Bern, Bern, Switzerland., Pritchard CEJ; Mouse Clinic for Cancer and Aging Research (MCCA), Transgenic Facility, The Netherlands Cancer Institute, 1066CX Amsterdam, The Netherlands., Huijbers IJ; Mouse Clinic for Cancer and Aging Research (MCCA), Transgenic Facility, The Netherlands Cancer Institute, 1066CX Amsterdam, The Netherlands., Fendler W; Department of Biostatistics and Translational Medicine, Medical University of Lodz, 92-215 Lodz, Poland.; Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA., Vens C; Department of Radiation Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.; Department of Head and Neck Oncology and Surgery, The Netherlands Cancer Institute, Amsterdam, The Netherlands., Rottenberg S; Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, 3012 Bern, Switzerland.; Division of Molecular Pathology, The Netherlands Cancer Institute, 1066CX Amsterdam, The Netherlands.; Bern Center for Precision Medicine, University of Bern, 3012 Bern, Switzerland.; Cancer Therapy Resistance Cluster, Department for BioMedical Research, University of Bern, 3012 Bern, Switzerland.
Jazyk:	angličtina
Zdroj:	Cancer research communications [Cancer Res Commun] 2022 Oct 26; Vol. 2 (10), pp. 1266-1281.
DOI:	10.1158/2767-9764.CRC-22-0208
Abstrakt:	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, e.g . 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 cis- 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 two-fold cisplatin maximum-tolerable dose. 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 WT mice. Moreover, we show that decreased expression of LRRC8A/D in head and neck squamous cell carcinoma patients, 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 cis- or car-boplatin-based chemotherapy. Competing Interests: Declaration of Interests The authors declare no competing interests. Conflict of interest: The authors declare no potential conflicts of interest.
Databáze:	MEDLINE
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