MYC induces CDK4/6 inhibitors resistance by promoting pRB1 degradation

Jian Ma, Lei Li, Bohan Ma, Tianjie Liu, Zixi Wang, Qi Ye, Yunhua Peng, Bin Wang, Yule Chen, Shan Xu, Ke Wang, Fabin Dang, Xinyang Wang, Zixuan Zeng, Yanlin Jian, Zhihua Ren, Yizeng Fan, Xudong Li, Jing Liu, Yang Gao, Wenyi Wei and Lei Li ()
Additional contact information
Jian Ma: The First Affiliated Hospital of Xi’an Jiaotong University
Lei Li: The First Affiliated Hospital of Xi’an Jiaotong University
Bohan Ma: The First Affiliated Hospital of Xi’an Jiaotong University
Tianjie Liu: The First Affiliated Hospital of Xi’an Jiaotong University
Zixi Wang: The First Affiliated Hospital of Xi’an Jiaotong University
Qi Ye: The First Affiliated Hospital of Xi’an Jiaotong University
Yunhua Peng: Xi’an Jiaotong University
Bin Wang: The First Affiliated Hospital of Xi’an Jiaotong University
Yule Chen: The First Affiliated Hospital of Xi’an Jiaotong University
Shan Xu: The First Affiliated Hospital of Xi’an Jiaotong University
Ke Wang: The First Affiliated Hospital of Xi’an Jiaotong University
Fabin Dang: Harvard Medical School
Xinyang Wang: The First Affiliated Hospital of Xi’an Jiaotong University
Zixuan Zeng: The First Affiliated Hospital of Xi’an Jiaotong University
Yanlin Jian: The First Affiliated Hospital of Xi’an Jiaotong University
Zhihua Ren: Kintor Parmaceutical, Inc
Yizeng Fan: The First Affiliated Hospital of Xi’an Jiaotong University
Xudong Li: The First Affiliated Hospital of Xi’an Jiaotong University
Jing Liu: The First Affiliated Hospital of Xi’an Jiaotong University
Yang Gao: The First Affiliated Hospital of Xi’an Jiaotong University
Wenyi Wei: Harvard Medical School
Lei Li: The First Affiliated Hospital of Xi’an Jiaotong University

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-45796-w

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