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

Carmen A Widmer1, Ismar Klebic1,2, Natalya Domanitskaya1

  • 1Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, 3012 Bern, Switzerland.

Cancer Research Communications
|December 5, 2022
PubMed

Insights

Loss of LRRC8A/D subunits reduces platinum drug uptake and efficacy in BRCA1-deficient cancers. LRRC8A/D expression predicts patient survival in head and neck cancers treated with platinum chemotherapy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Platinum-based chemotherapy is effective for cancers with DNA damage response defects, such as those with BRCA1 mutations.
  • Predictive biomarkers for platinum (Pt) drug response are needed for clinical application.
  • Volume-regulated anion channels (LRRC8A/D) facilitate Pt drug uptake in BRCA1-proficient cells.

Purpose of the Study:

  • To investigate the role of LRRC8A and LRRC8D in platinum drug uptake and efficacy in BRCA1-deficient cancer models.
  • To establish a mouse model for intensified platinum-based chemotherapy.
  • To correlate LRRC8A/D expression with patient outcomes in head and neck squamous cell carcinoma treated with platinum chemoradiotherapy.

Main Methods:

  • Utilized BRCA1;p53-deficient mouse mammary tumor cells to assess platinum drug uptake and DNA damage.
  • Generated Lrrc8a and Lrrc8d knockout mouse models.
  • Administered intensified cisplatin doses to evaluate tumor eradication in wild-type and knockout mice.
  • Analyzed LRRC8A/D expression in head and neck squamous cell carcinoma patient cohorts.

Main Results:

  • Loss of LRRC8A or LRRC8D significantly reduced cisplatin and carboplatin uptake, DNA damage, and in vivo drug resistance in BRCA1;p53-deficient mouse cells.
  • Lrrc8d knockout mice tolerated higher cisplatin doses, enabling the establishment of an intensified chemotherapy model.
  • Increased cisplatin doses eradicated BRCA1;p53-deficient tumors in the mouse model, unlike in wild-type mice.
  • Decreased LRRC8A/D expression in head and neck squamous cell carcinoma patients correlated with reduced overall survival and diminished efficacy of high-dose cisplatin treatment.

Conclusions:

  • LRRC8A and LRRC8D are critical for platinum drug uptake and efficacy in BRCA1-deficient cancers.
  • LRRC8D-deficient mice provide a valuable model for intensified platinum-based chemotherapy research.
  • LRRC8A/D expression levels can serve as predictive biomarkers for platinum chemotherapy success, particularly in head and neck squamous cell carcinoma.
Keywords:
BRCA1HNSCCLRRC8ALRRC8DPlatinum drug resistanceVRACbreast cancergenetically engineered mouse modelhigh-dose chemotherapy

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