2. Academic Validation
  3. Novel Insights into the Molecular Regulation of Ribonucleotide Reductase in Adrenocortical Carcinoma Treatment

Novel Insights into the Molecular Regulation of Ribonucleotide Reductase in Adrenocortical Carcinoma Treatment

  • Cancers (Basel). 2021 Aug 20;13(16):4200. doi: 10.3390/cancers13164200.
Christina Bothou 1 2,  Ashish Sharma 1,  Adrian Oo 3,  Baek Kim 3 4,  Pal Perge 5,  Peter Igaz 5 6,  Cristina L Ronchi 7 8 9,  Igor Shapiro 1,  Constanze Hantel 1 10
Affiliations

Affiliations

  • 1 Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital Zurich (USZ), University of Zurich (UZH), CH-8091 Zurich, Switzerland.
  • 2 Competence Centre of Personalized Medicine, Molecular and Translational Biomedicine PhD Program, University of Zurich (UZH), CH-8006 Zurich, Switzerland.
  • 3 Department of Pediatrics, School of Medicine, Emory University, Atlanta, GA 30322, USA.
  • 4 Center for Drug Discovery, Children's Healthcare of Atlanta, Atlanta, GA 30322, USA.
  • 5 Department of Endocrinology, Department of Internal Medicine and Oncology, Faculty of Medicine, Semmelweis University, H-1083 Budapest, Hungary.
  • 6 MTA-SE Molecular Medicine Research Group, H-1083 Budapest, Hungary.
  • 7 Division of Endocrinology and Diabetes, Department of Medicine I, University Hospital of Wuerzburg, University of Wuerzburg, 97080 Wuerzburg, Germany.
  • 8 Institute of Metabolism and Systems Research, University of Birmingham, Birmingham B15 2TT, UK.
  • 9 Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham B15 2TT, UK.
  • 10 Medizinische Klinik und Poliklinik III, University Hospital Carl Gustav Carus Dresden, 01307 Dresden, Germany.
PMID: 34439352 DOI: 10.3390/cancers13164200
Abstract

Current systemic treatment options for patients with adrenocortical carcinomas (ACCs) are far from being satisfactory. DNA damage/repair mechanisms, which involve, e.g., ataxia-telangiectasia-mutated (ATM) and ataxia-telangiectasia/Rad3-related (ATR) protein signaling or ribonucleotide reductase subunits M1/M2 (RRM1/RRM2)-encoded ribonucleotide reductase (RNR) activation, commonly contribute to drug resistance. Moreover, the regulation of RRM2b, the p53-induced alternative to RRM2, is of unclear importance for ACC. Upon extensive drug screening, including a large panel of chemotherapies and molecular targeted inhibitors, we provide strong evidence for the anti-tumoral efficacy of combined gemcitabine (G) and cisplatin (C) treatment against the adrenocortical cell lines NCI-H295R and MUC-1. However, accompanying induction of RRM1, RRM2, and RRM2b expression also indicated developing G resistance, a frequent side effect in clinical patient care. Interestingly, this effect was partially reversed upon addition of C. We confirmed our findings for RRM2 protein, RNR-dependent dATP levels, and modulations of related ATM/ATR signaling. Finally, we screened for complementing inhibitors of the DNA damage/repair system targeting RNR, Wee1, Chk1/2, ATR, and ATM. Notably, the combination of G, C, and the dual RRM1/RRM2 inhibitor COH29 resulted in previously unreached total cell killing. In summary, we provide evidence that RNR-modulating therapies might represent a new therapeutic option for ACC.

Keywords

COH29; RNR; RRM2; adrenocortical carcinoma; adrenocortical cell line.

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