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

Author information

Affiliations

  • 1. 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.
      Authors
    • Li N 1
    • Sun YJ 1
    • Zhang JS 1
    (3 authors)
  • 2. 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.
      Authors
    • Huang LY 2
    (1 author)
  • 3. Department of Radiotherapy, Cancer Center, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, China; Shantou University Medical College, Shantou University, Shantou, Guangdong 515000, China.
      Authors
    • Li RR 3
    • Yang L 3
    (2 authors)
  • 4. State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
      Authors
    • Qiu AH 4
    • Wang J 4
    (2 authors)

Drug Resistance Updates : Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy, 21 Oct 2024, 78:101161
https://doi.org/10.1016/j.drup.2024.101161 PMID: 39499997 

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.

Full text links 

Read article at publisher's site: https://doi.org/10.1016/j.drup.2024.101161

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Funding 

Funders who supported this work.

Basic and Applied Basic Research Foundation of Guangdong Province (2)

National Natural Science Foundation of China (4)

Science and Technology Planning Project of Fuzhou (1)