@article{BothouSharmaOoetal.2021,
  author    = {Bothou, Christina and Sharma, Ashish and Oo, Adrian and Kim, Baek and Perge, Pal and Igaz, Peter and Ronchi, Cristina L. and Shapiro, Igor and Hantel, Constanze},
  title     = {Novel insights into the molecular regulation of ribonucleotide reductase in adrenocortical carcinoma treatment},
  series = {Cancers},
  volume    = {13},
  journal   = {Cancers},
  number    = {16},
  issn      = {2072-6694},
  doi       = {10.3390/cancers13164200},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-245132},
  year      = {2021},
  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.},
  language  = {en}
}