Department of Molecular and Functional Dynamics, Graduate School of Medicine, Tohoku University, 2-1, Seiryoumachi, Aoba-ku, Sendai, 980-8575, Japan.
Department of Breast and Endocrine Surgical Oncology, Graduate School of Medicine, Tohoku University, Sendai, Japan.
Breast Cancer. 2020 Sep;27(5):963-972. doi: 10.1007/s12282-020-01090-3. Epub 2020 Apr 15.
Cyclin-dependent kinase (CDK) 4/6 inhibitors represent a significant advancement in the treatment of estrogen receptor (ER)-positive human epidermal growth factor receptor 2-negative advanced breast cancer. However, mechanisms of alterations after acquired resistance to CDK4/6 inhibitors and the optimal treatment options are still not established.
Abemaciclib-resistant cell lines were established from the models of estrogen deprivation-resistant cell lines which retained ER expression and activated ER function derived from MCF-7 breast cancer cell lines. Ribocilib-resistant cell lines were established in the same method as previously reported.
Both abemaciclib- and ribociclib-resistant cell lines showed decreased ER expression. ER transcriptional activity was maintained in these cell lines; however, the sensitivity to 4-hydroxytamoxifen and fulvestrant was almost completely lost. These cell lines did not exhibit any ERα gene mutation. Abemaciclib-resistant cell lines demonstrated low sensitivity to other CDK4/6 inhibitors; sensitivities to PI3K inhibitor, mTOR inhibitor, and chemotherapeutic drugs were maintained.
Dependence on ER signaling appears to decrease after the development of acquired resistance to CDK4/6 inhibitors. Further, CDK4/6 inhibitor-resistant cells acquired cross-resistance to other CDK4/6 inhibitors, PI3K/Akt/mTOR inhibitor therapy and chemotherapeutic drugs might serve as optimal treatment options for such breast cancers.
细胞周期蛋白依赖性激酶（CDK）4/6 抑制剂的出现代表了治疗雌激素受体（ER）阳性人表皮生长因子受体 2 阴性晚期乳腺癌的重大进展。然而，获得 CDK4/6 抑制剂耐药后发生改变的机制以及最佳治疗选择仍未确立。
从 MCF-7 乳腺癌细胞系来源的雌激素剥夺耐药细胞系中建立保留 ER 表达并激活 ER 功能的模型，建立阿贝西利耐药细胞系。采用与先前报道相同的方法建立瑞博西利耐药细胞系。
阿贝西利和瑞博西利耐药细胞系均表现出 ER 表达降低。这些细胞系中 ER 转录活性得以维持，但对 4-羟基他莫昔芬和氟维司群的敏感性几乎完全丧失。这些细胞系未显示任何 ERα 基因突变。阿贝西利耐药细胞系对其他 CDK4/6 抑制剂的敏感性降低；对 PI3K 抑制剂、mTOR 抑制剂和化疗药物的敏感性保持不变。
在对 CDK4/6 抑制剂产生获得性耐药后，对 ER 信号的依赖似乎降低。此外，CDK4/6 抑制剂耐药细胞获得对其他 CDK4/6 抑制剂、PI3K/Akt/mTOR 抑制剂治疗和化疗药物的交叉耐药，这些可能是此类乳腺癌的最佳治疗选择。
