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

Autor: Li N; 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., Sun YJ; 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., Huang LY; 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., Li RR; 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., Zhang JS; 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., Qiu AH; State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, China., Wang J; State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, China. Electronic address: wangj@sysucc.org.cn., Yang L; 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. Electronic address: yanglu0515@outlook.com.
Jazyk: angličtina
Zdroj: Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy [Drug Resist Updat] 2024 Oct 21; Vol. 78, pp. 101161. Date of Electronic Publication: 2024 Oct 21.
DOI: 10.1016/j.drup.2024.101161
Abstrakt: 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.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: