Bothou Christina, Sharma Ashish, Oo Adrian, Kim Baek, Perge Pal, Igaz Peter, Ronchi Cristina L, Shapiro Igor, Hantel Constanze
Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital Zurich (USZ), University of Zurich (UZH), CH-8091 Zurich, Switzerland.
Competence Centre of Personalized Medicine, Molecular and Translational Biomedicine PhD Program, University of Zurich (UZH), CH-8006 Zurich, Switzerland.
Cancers (Basel). 2021 Aug 20;13(16):4200. doi: 10.3390/cancers13164200.
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.
目前，肾上腺皮质癌（ACC）患者的全身治疗选择远不能令人满意。DNA损伤/修复机制，例如涉及共济失调毛细血管扩张突变（ATM）和共济失调毛细血管扩张症/ Rad3相关（ATR）蛋白信号传导或核糖核苷酸还原酶亚基M1 / M2（RRM1 / RRM2）编码的核糖核苷酸还原酶（RNR）激活，通常会导致耐药性。此外，RRM2b（p53诱导的RRM2替代物）的调节对ACC的重要性尚不清楚。在进行广泛的药物筛选后，包括大量的化疗药物和分子靶向抑制剂，我们提供了强有力的证据，证明吉西他滨（G）和顺铂（C）联合治疗对肾上腺皮质细胞系NCI-H295R和MUC-1具有抗肿瘤疗效。然而，伴随的RRM1、RRM2和RRM2b表达的诱导也表明出现了G耐药性，这是临床患者护理中常见的副作用。有趣的是，加入C后这种效应部分得到逆转。我们证实了我们关于RRM2蛋白、RNR依赖性dATP水平以及相关ATM / ATR信号传导调节的发现。最后，我们筛选了针对RNR、Wee1、CHK1 / 2、ATR和ATM的DNA损伤/修复系统的互补抑制剂。值得注意的是，G、C和双重RRM1 / RRM2抑制剂COH29的联合使用导致了前所未有的全细胞杀伤。总之，我们提供的证据表明，调节RNR的疗法可能是ACC的一种新的治疗选择。
