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

• Type of Material: Article
• Authors: Christina Bothou, Univ Zurich UZH; Ashish Sharma, Emory University; Adrian Oo, Emory University; Baek Kim, Emory University; Pal Perge, Semmelweis University; Peter Igaz, Semmelweis University; Cristina L Ronchi, University of Wurzburg; Igor Shapiro, University of Zurich (UZH); Constanze Hantel, University of Zurich (UZH)
• Language: English
• Date: 2021-08-01
• Publisher: MDPI
• Publication Version: Final Published Version
• Copyright Statement: © 2021 by the authors.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.3390/cancers13164200
• Title of Journal or Parent Work: CANCERS
• Volume: 13
• Issue: 16
• Grant/Funding Information: This work was supported by the Uniscientia Foundation (Keyword Tumor Model) to C.H. Moreover, the work received funding from NIH AI150451 and NIH AI162633 to B.K.
• Keywords: Oncology; MARKER; GEMCITABINE; RRM2; EFFICACY; MULTICENTER; Life Sciences & Biomedicine; Science & Technology; EXPRESSION; CISPLATIN; adrenocortical cell line; CLASSIFICATION; MITOTANE; COH29; RNR; adrenocortical carcinoma; CHEMOTHERAPY; CANCER-CELL GROWTH
• Research Categories: Health Sciences, Nutrition

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.