2. Academic Validation
  3. MYC induces CDK4/6 inhibitors resistance by promoting pRB1 degradation

MYC induces CDK4/6 inhibitors resistance by promoting pRB1 degradation

  • Nat Commun. 2024 Feb 29;15(1):1871. doi: 10.1038/s41467-024-45796-w.
Jian Ma # 1 2 3,  Lei Li # 1 2 3,  Bohan Ma # 1 2 3,  Tianjie Liu 1 2 3,  Zixi Wang 1 2 3,  Qi Ye 1 2 3,  Yunhua Peng 4,  Bin Wang 1 2 3,  Yule Chen 1 2 3,  Shan Xu 1 2 3,  Ke Wang 1 2 3,  Fabin Dang 5,  Xinyang Wang 1 2 3,  Zixuan Zeng 1 2 3,  Yanlin Jian 1 2 3,  Zhihua Ren 6,  Yizeng Fan 1 2 3,  Xudong Li 1 2 3,  Jing Liu 1 2 3,  Yang Gao 1 2 3,  Wenyi Wei 5,  Lei Li 7 8 9
Affiliations

Affiliations

  • 1 Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China.
  • 2 Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, 710061, China.
  • 3 Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China.
  • 4 Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, 710049, China.
  • 5 Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02115, USA.
  • 6 Kintor Parmaceutical, Inc, Suzhou, 215123, China.
  • 7 Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China. lilydr@163.com.
  • 8 Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, 710061, China. lilydr@163.com.
  • 9 Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China. lilydr@163.com.
  • # Contributed equally.
PMID: 38424044 DOI: 10.1038/s41467-024-45796-w
Abstract

CDK4/6 inhibitors (CDK4/6i) show Anticancer activity in certain human malignancies, such as breast Cancer. However, their application to other tumor types and intrinsic resistance mechanisms are still unclear. Here, we demonstrate that MYC amplification confers resistance to CDK4/6i in bladder, prostate and breast Cancer cells. Mechanistically, MYC binds to the promoter of the E3 ubiquitin Ligase KLHL42 and enhances its transcription, leading to RB1 deficiency by inducing both phosphorylated and total pRB1 ubiquitination and degradation. We identify a compound that degrades MYC, A80.2HCl, which induces MYC degradation at nanomolar concentrations, restores pRB1 protein levels and re-establish sensitivity of MYC high-expressing Cancer cells to CDK4/6i. The combination of CDK4/6i and A80.2HCl result in marked regression in tumor growth in vivo. Altogether, these results reveal the molecular mechanisms underlying MYC-induced resistance to CDK4/6i and suggest the utilization of the MYC degrading molecule A80.2HCl to potentiate the therapeutic efficacy of CDK4/6i.

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