Knappskog Stian, Berge Elisabet O, Chrisanthar Ranjan, Geisler Stephanie, Staalesen Vidar, Leirvaag Beryl, Yndestad Synnøve, de Faveri Elise, Karlsen Bård O, Wedge David C, Akslen Lars A, Lilleng Peer K, Løkkevik Erik, Lundgren Steinar, Østenstad Bjørn, Risberg Terje, Mjaaland Ingvild, Aas Turid, Lønning Per E
Section of Oncology, Department of Clinical Science, University of Bergen, Norway; Department of Oncology, Haukeland University Hospital, Bergen, Norway.
Section of Oncology, Department of Clinical Science, University of Bergen, Norway; Department of Oncology, Haukeland University Hospital, Bergen, Norway.
Mol Oncol. 2015 Oct;9(8):1553-64. doi: 10.1016/j.molonc.2015.04.008. Epub 2015 May 8.
Chemoresistance is the main obstacle to cancer cure. Contrasting studies focusing on single gene mutations, we hypothesize chemoresistance to be due to inactivation of key pathways affecting cellular mechanisms such as apoptosis, senescence, or DNA repair. In support of this hypothesis, we have previously shown inactivation of either TP53 or its key activators CHK2 and ATM to predict resistance to DNA damaging drugs in breast cancer better than TP53 mutations alone. Further, we hypothesized that redundant pathway(s) may compensate for loss of p53-pathway signaling and that these are inactivated as well in resistant tumour cells. Here, we assessed genetic alterations of the retinoblastoma gene (RB1) and its key regulators: Cyclin D and E as well as their inhibitors p16 and p27. In an exploratory cohort of 69 patients selected from two prospective studies treated with either doxorubicin monotherapy or 5-FU and mitomycin for locally advanced breast cancers, we found defects in the pRB-pathway to be associated with therapy resistance (p-values ranging from 0.001 to 0.094, depending on the cut-off value applied to p27 expression levels). Although statistically weaker, we observed confirmatory associations in a validation cohort from another prospective study (n = 107 patients treated with neoadjuvant epirubicin monotherapy; p-values ranging from 7.0 × 10(-4) to 0.001 in the combined data sets). Importantly, inactivation of the p53-and the pRB-pathways in concert predicted resistance to therapy more strongly than each of the two pathways assessed individually (exploratory cohort: p-values ranging from 3.9 × 10(-6) to 7.5 × 10(-3) depending on cut-off values applied to ATM and p27 mRNA expression levels). Again, similar findings were confirmed in the validation cohort, with p-values ranging from 6.0 × 10(-7) to 6.5 × 10(-5) in the combined data sets. Our findings strongly indicate that concomitant inactivation of the p53- and pRB- pathways predict resistance towards anthracyclines and mitomycin in breast cancer in vivo.
化疗耐药是癌症治愈的主要障碍。与聚焦于单基因突变的研究不同，我们推测化疗耐药是由于影响细胞机制（如细胞凋亡、衰老或DNA修复）的关键信号通路失活所致。为支持这一假设，我们之前已表明，TP53及其关键激活因子CHK2和ATM的失活比单独的TP53突变能更好地预测乳腺癌对DNA损伤药物的耐药性。此外，我们推测冗余信号通路可能会补偿p53信号通路的缺失，而这些冗余信号通路在耐药肿瘤细胞中也会失活。在此，我们评估了视网膜母细胞瘤基因（RB1）及其关键调节因子的基因改变：细胞周期蛋白D和E以及它们的抑制剂p16和p27。在一个探索性队列中，我们从两项前瞻性研究中选取了69例接受阿霉素单药治疗或5-氟尿嘧啶与丝裂霉素联合治疗的局部晚期乳腺癌患者，发现pRB信号通路缺陷与治疗耐药相关（p值范围为0.001至0.094，具体取决于应用于p27表达水平的临界值）。尽管统计学意义较弱，但我们在另一项前瞻性研究的验证队列中观察到了验证性关联（n = 107例接受新辅助表柔比星单药治疗的患者；合并数据集中p值范围为7.0×10⁻⁴至0.001）。重要的是，p53和pRB信号通路同时失活比单独评估这两条信号通路中的任何一条更能强烈预测对治疗的耐药性（探索性队列：根据应用于ATM和p27 mRNA表达水平的临界值，p值范围为3.9×10⁻⁶至7.5×10⁻³）。同样，在验证队列中也证实了类似的发现，合并数据集中p值范围为6.0×10⁻⁷至6.5×10⁻⁵。我们的研究结果强烈表明，p53和pRB信号通路同时失活可预测乳腺癌体内对蒽环类药物和丝裂霉素的耐药性。
Zotero 插件
