Fasting-mimicking diet potentiates anti-tumor effects of CDK4/6 inhibitors against breast cancer by suppressing NRAS- and IGF1-mediated mTORC1 signaling

IF 15.8 1区 医学 Q1 PHARMACOLOGY & PHARMACY Drug Resistance Updates Pub Date : 2024-10-21 DOI:10.1016/j.drup.2024.101161
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Abstract

Aims

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.

Methods

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.

Results

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.

Conclusions

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.
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模拟空腹饮食通过抑制 NRAS 和 IGF1 介导的 mTORC1 信号传导,增强 CDK4/6 抑制剂对乳腺癌的抗肿瘤作用
目的 细胞周期蛋白依赖性激酶4/6抑制剂(CDK4/6i)的获得性耐药性经常出现,三阴性乳腺癌(TNBC)中含CDK4/6i的疗法仍有待确定。结果CDK4/6i耐药细胞中的mTOR通路被激活,抑制mTORC1可恢复其敏感性。禁食模拟饮食(FMD)可通过抑制 mTORC1 信号传导增强抗癌药物的活性,我们对 FMD 进行了评估,发现 FMD 可恢复 CDK4/6i- 耐药细胞对阿巴西利(abemaciclib)的敏感性,并增强 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共同抑制了IGF1和RAS的水平。结论我们的数据表明,FMD 可通过降低 IGF1 和 RAS 水平抑制 mTORC1 信号传导,从而克服耐药性并增强 CDK4/6i 的抗肿瘤作用,这为临床研究 FMD-CDK4/6i 治疗乳腺癌的潜在策略提供了理论依据。
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来源期刊
Drug Resistance Updates
Drug Resistance Updates 医学-药学
CiteScore
26.20
自引率
11.90%
发文量
32
审稿时长
29 days
期刊介绍: Drug Resistance Updates serves as a platform for publishing original research, commentary, and expert reviews on significant advancements in drug resistance related to infectious diseases and cancer. It encompasses diverse disciplines such as molecular biology, biochemistry, cell biology, pharmacology, microbiology, preclinical therapeutics, oncology, and clinical medicine. The journal addresses both basic research and clinical aspects of drug resistance, providing insights into novel drugs and strategies to overcome resistance. Original research articles are welcomed, and review articles are authored by leaders in the field by invitation. Articles are written by leaders in the field, in response to an invitation from the Editors, and are peer-reviewed prior to publication. Articles are clear, readable, and up-to-date, suitable for a multidisciplinary readership and include schematic diagrams and other illustrations conveying the major points of the article. The goal is to highlight recent areas of growth and put them in perspective. *Expert reviews in clinical and basic drug resistance research in oncology and infectious disease *Describes emerging technologies and therapies, particularly those that overcome drug resistance *Emphasises common themes in microbial and cancer research
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