Chiappa Michela, Guffanti Federica, Grasselli Chiara, Panini Nicolò, Corbelli Alessandro, Fiordaliso Fabio, Damia Giovanna
Department of Experimental Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Via M. Negri 2, 20156 Milan, Italy.
Department of Biochemistry and Molecular Pharmacology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Via M. Negri 2, 20156 Milan, Italy.
Int J Mol Sci. 2024 Mar 6;25(5):3049. doi: 10.3390/ijms25053049.
Platinum compounds are very active in first-line treatments of ovarian carcinoma. In fact, high rates of complete remission are achieved, but most patients eventually relapse with resistant disease. Many mechanisms underlying the platinum-resistant phenotype have been reported. However, there are no data in the same isogenic cell system proficient and deficient in homologous recombination (HR) on platinum-acquired resistance that might unequivocally clarify the most important mechanism associated with resistance. We generated and characterized cisplatin (DDP)-resistant murine ovarian ID8 cell lines in a HR-deficient and -proficient background. Specific upregulation of the NER pathway in the HR-proficient and -resistant cells and partial restoration of HR in Brca1-/--resistant cells were found. Combinations of different inhibitors of the DNA damage response pathways with cisplatin were strongly active in both resistant and parental cells. The data from the ID8 isogenic system are in line with current experimental and clinical evidence and strongly suggest that platinum resistance develops in different ways depending on the cell DNA repair status (i.e., HR-proficient or HR-deficient), and the upregulation and/or restoration of repair pathways are major determinants of DDP resistance.
铂类化合物在卵巢癌的一线治疗中非常有效。事实上，能实现较高的完全缓解率，但大多数患者最终会复发为耐药性疾病。已经报道了许多铂耐药表型的潜在机制。然而，在同源重组（HR） proficient和deficient的同基因细胞系统中，关于铂获得性耐药的研究尚无数据，这些数据可能明确阐明与耐药相关的最重要机制。我们在HR-deficient和-proficient背景下生成并鉴定了顺铂（DDP）耐药的小鼠卵巢ID8细胞系。发现在HR-proficient和耐药细胞中NER途径的特异性上调以及在Brca1-/-耐药细胞中HR的部分恢复。不同DNA损伤反应途径抑制剂与顺铂的联合在耐药细胞和亲本细胞中均具有很强的活性。来自ID8同基因系统的数据与当前的实验和临床证据一致，并强烈表明铂耐药性根据细胞DNA修复状态（即HR-proficient或HR-deficient）以不同方式发展，并且修复途径的上调和/或恢复是DDP耐药性的主要决定因素。
