Li Ning, Sun Ya-Jie, Huang Li-Yun, Li Rong-Rong, Zhang Jun-Sheng, Qiu Ai-Hua, Wang Jing, Yang Lu
Department of Breast Oncology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
Department of Pathology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
Drug Resist Updat. 2025 Jan;78:101161. doi: 10.1016/j.drup.2024.101161. Epub 2024 Oct 21.
Acquired resistance to cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) frequently emerges, and CDK4/6i-containing therapies in triple-negative breast cancer (TNBC) remain to be determined.
RNA-sequencing, cell viability analysis, immunoblotting, siRNA transfection et al. were used to investigate and verify the resistance mechanism. BALB/c nude mice xenograft models and spontaneous MMTV-PyMT models were used to explore in vivo efficacy.
The mTOR pathway was activated in acquired CDK4/6i-resistant cells and inhibition of mTORC1 restored the sensitivity. While fasting-mimicking diet (FMD) enhances the activity of anticancer agents by inhibiting the mTORC1 signaling, we assessed FMD and found that FMD restored the sensitivity of CDK4/6i-resistant cells to abemaciclib and potentiated the anti-tumor activity of CDK4/6i in TNBC. The anti-tumor effects of FMD and/or CDK4/6i were accompanied by the downregulation of S6 phosphorylation. FMD cooperated with CDK4/6i to suppress the levels of IGF1 and RAS. The combination of FMD and abemaciclib also led to a potent inhibition of tumor growth in spontaneous transgenic MMTV-PyMT mouse models.
Our data demonstrate that FMD overcomes resistance and potentiates the anti-tumor effect of CDK4/6i by inhibiting mTORC1 signaling via lowering the levels of IGF1 and RAS, providing the rationale for clinical investigation of a potential FMD-CDK4/6i strategy in breast cancer.
对细胞周期蛋白依赖性激酶4/6抑制剂（CDK4/6i）的获得性耐药经常出现，三阴性乳腺癌（TNBC）中含CDK4/6i的治疗方案仍有待确定。
采用RNA测序、细胞活力分析、免疫印迹、小干扰RNA转染等方法研究和验证耐药机制。利用BALB/c裸鼠异种移植模型和自发性MMTV-PyMT模型探索体内疗效。
在获得性CDK4/6i耐药细胞中mTOR通路被激活，抑制mTORC1可恢复敏感性。禁食模拟饮食（FMD）通过抑制mTORC1信号增强抗癌药物的活性，我们评估了FMD，发现FMD恢复了CDK4/6i耐药细胞对阿贝西利的敏感性，并增强了CDK4/6i在TNBC中的抗肿瘤活性。FMD和/或CDK4/6i的抗肿瘤作用伴随着S6磷酸化的下调。FMD与CDK4/6i协同作用以抑制IGF1和RAS的水平。FMD与阿贝西利联合使用还导致自发性转基因MMTV-PyMT小鼠模型中的肿瘤生长受到有效抑制。
我们的数据表明，FMD通过降低IGF1和RAS的水平抑制mTORC1信号，从而克服耐药性并增强CDK4/6i的抗肿瘤作用，为乳腺癌中潜在的FMD-CDK4/6i策略的临床研究提供了理论依据。
