2. Academic Validation
  3. Dual Inhibition of CDK4/6 and CDK7 Suppresses Triple-Negative Breast Cancer Progression via Epigenetic Modulation of SREBP1-Regulated Cholesterol Metabolism

Dual Inhibition of CDK4/6 and CDK7 Suppresses Triple-Negative Breast Cancer Progression via Epigenetic Modulation of SREBP1-Regulated Cholesterol Metabolism

  • Adv Sci (Weinh). 2025 Feb;12(5):e2413103. doi: 10.1002/advs.202413103.
Yilan Yang 1 2 3 4,  Jiatao Liao 1 2 3 4,  Zhe Pan 1 2 3 4,  Jin Meng 1 2 3 4,  Li Zhang 1 2 3 4,  Wei Shi 1 2 3 4,  Xiaofang Wang 1 2 3 4,  Xiaomeng Zhang 1 2 3 4,  Zhirui Zhou 2 5,  Jurui Luo 6,  Xingxing Chen 1 2 3 4,  Zhaozhi Yang 1 2 3 4,  Xin Mei 1 2 3 4,  Jinli Ma 1 2 3 4,  Zhen Zhang 1 2 3 4,  Yi-Zhou Jiang 2 7,  Zhi-Min Shao 2 7,  Fei Xavier Chen 1 8,  Xiaoli Yu 1 2 3 4,  Xiaomao Guo 1 2 3 4
Affiliations

Affiliations

  • 1 Department of Radiation Oncology, Fudan University Shanghai Cancer Center, No.270 Dong'an Road, Shanghai, 200032, China.
  • 2 Department of Oncology, Shanghai Medical College, Fudan University, No.270 Dong'an Road, Shanghai, 200032, China.
  • 3 Shanghai Clinical Research Center for Radiation Oncology, No.270 Dong'an Road, Shanghai, 200032, China.
  • 4 Shanghai Key Laboratory of Radiation Oncology, No.270 Dong'an Road, Shanghai, 200032, China.
  • 5 Radiation Oncology Center, Huashan Hospital, No.12 Wulumuqi Middle Road, Shanghai, 200040, China.
  • 6 Department of Radiation Oncology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, No.1630 Dongfang Road, Shanghai, 200127, China.
  • 7 Department of Breast Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong'an Road, Shanghai, 200032, China.
  • 8 Fudan University Shanghai Cancer Center, Institutes of Biomedical Sciences, State Key Laboratory of Genetic Engineering, Shanghai Key Laboratory of Medical Epigenetics, Shanghai Key Laboratory of Radiation Oncology, Fudan University, No.131 Dong'an Road, Shanghai, 200032, China.
PMID: 39656925 DOI: 10.1002/advs.202413103
Abstract

Inhibitors targeting cyclin-dependent kinases 4 and 6 (CDK4/6) to block cell cycle progression have been effective in treating hormone receptor-positive breast Cancer, but triple-negative breast Cancer (TNBC) remains largely resistant, limiting their clinical applicability. The study reveals that transcription regulator cyclin-dependent kinase7 (CDK7) is a promising target to circumvent TNBC's inherent resistance to CDK4/6 inhibitors. Combining CDK4/6 and CDK7 inhibitors significantly enhances therapeutic effectiveness, leading to a marked decrease in Cholesterol biosynthesis within cells. This effect is achieved through reduced activity of the transcription factor forkhead box M1 (FOXM1), which normally increases Cholesterol production by inducing SREBF1 expression. Furthermore, this dual inhibition strategy attenuates the recruitment of sterol regulatory element binding transcription factor 1 (SREBP1) and p300 to genes essential for Cholesterol synthesis, thus hindering tumor growth. This research is corroborated by an in-house cohort showing lower survival rates in TNBC patients with higher Cholesterol production gene activity. This suggests a new treatment approach for TNBC by simultaneously targeting CDK4/6 and CDK7, warranting additional clinical trials.

Keywords

CDK4/6; CDK7; breast cancer; cholesterol metabolism.

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