Alexander Angela, Karakas Cansu, Chen Xian, Carey Jason P W, Yi Min, Bondy Melissa, Thompson Patricia, Cheung Kwok Leung, Ellis Ian O, Gong Yun, Krishnamurthy Savitri, Alvarez Ricardo H, Ueno Naoto T, Hunt Kelly K, Keyomarsi Khandan
Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, Houston, Texas, USA.
Oncotarget. 2017 Feb 28;8(9):14897-14911. doi: 10.18632/oncotarget.14689.
Inflammatory breast cancer (IBC) is a virulent form of breast cancer, and novel treatment strategies are urgently needed. Immunohistochemical analysis of tumors from women with a clinical diagnosis of IBC (n = 147) and those with non-IBC breast cancer (n = 2510) revealed that, whereas in non-IBC cases cytoplasmic cyclin E was highly correlated with poor prognosis (P < 0.001), in IBC cases both nuclear and cytoplasmic cyclin E were indicative of poor prognosis. These results underscored the utility of the cyclin E/CDK2 complex as a novel target for treatment. Because IBC cell lines were highly sensitive to the CDK2 inhibitors dinaciclib and meriolin 5, we developed a high-throughput survival assay (HTSA) to design novel sequential combination strategies based on the presence of cyclin E and CDK2. Using a 14-cell-line panel, we found that dinaciclib potentiated the activity of DNA-damaging chemotherapies treated in a sequence of dinaciclib followed by chemotherapy, whereas this was not true for paclitaxel. We also identified a signature of DNA repair-related genes that are downregulated by dinaciclib, suggesting that global DNA repair is inhibited and that prolonged DNA damage leads to apoptosis. Taken together, our findings argue that CDK2-targeted combinations may be viable strategies in IBC worthy of future clinical investigation.
炎性乳腺癌（IBC）是一种侵袭性很强的乳腺癌，迫切需要新的治疗策略。对临床诊断为IBC的女性患者（n = 147）和非IBC乳腺癌患者（n = 2510）的肿瘤进行免疫组织化学分析发现，在非IBC病例中，细胞质细胞周期蛋白E与预后不良高度相关（P < 0.001），而在IBC病例中，细胞核和细胞质细胞周期蛋白E均提示预后不良。这些结果强调了细胞周期蛋白E/细胞周期蛋白依赖性激酶2（CDK2）复合物作为一种新的治疗靶点的实用性。由于IBC细胞系对CDK2抑制剂dinaciclib和meriolin 5高度敏感，我们开发了一种高通量生存分析（HTSA），以根据细胞周期蛋白E和CDK2的存在设计新的序贯联合治疗策略。使用一个包含14种细胞系的细胞组，我们发现dinaciclib增强了DNA损伤化疗药物的活性，采用dinaciclib后接化疗的顺序给药方式，而对于紫杉醇则并非如此。我们还鉴定出一组DNA修复相关基因的特征，这些基因被dinaciclib下调，这表明整体DNA修复受到抑制，延长的DNA损伤导致细胞凋亡。综上所述，我们的研究结果表明，以CDK2为靶点的联合治疗可能是IBC中可行的策略，值得未来进行临床研究。
