The RNA-binding protein LRPPRC promotes resistance to CDK4/6 inhibition in lung cancer

Wei Zhou, Wenxi Wang, Yuxin Liang, Ruibin Jiang, Fensheng Qiu, Xiying Shao, Yang Liu, Le Fang, Maowei Ni, Chenhuan Yu, Yue Zhao, Weijia Huang, Jiong Li, Michael J. Donovan, Lina Wang, Juan Ni, Dachi Wang, Ting Fu, Jianguo Feng, Xiaojia Wang, Weihong Tan () and Xiaohong Fang ()
Additional contact information
Wei Zhou: Chinese Academy of Sciences
Wenxi Wang: Chinese Academy of Sciences
Yuxin Liang: Chinese Academy of Science
Ruibin Jiang: Chinese Academy of Sciences
Fensheng Qiu: Chinese Academy of Sciences
Xiying Shao: Chinese Academy of Sciences
Yang Liu: Chinese Academy of Science
Le Fang: Chinese Academy of Sciences
Maowei Ni: Chinese Academy of Sciences
Chenhuan Yu: Chinese Academy of Sciences
Yue Zhao: Chinese Academy of Sciences
Weijia Huang: Chinese Academy of Sciences
Jiong Li: Virginia Commonwealth University
Michael J. Donovan: Chinese Academy of Sciences
Lina Wang: Chinese Academy of Science
Juan Ni: Chinese Academy of Sciences
Dachi Wang: Chinese Academy of Sciences
Ting Fu: Chinese Academy of Sciences
Jianguo Feng: Chinese Academy of Sciences
Xiaojia Wang: Chinese Academy of Sciences
Weihong Tan: Chinese Academy of Sciences
Xiaohong Fang: Chinese Academy of Sciences

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: Abstract Kinase inhibitors against Cyclin Dependent Kinase 4 and 6 (CDK4/6i) are promising cancer therapeutic drugs. However, their effects are limited by primary or acquired resistance in virtually all tumor types. Here, we demonstrate that Leucine Rich Pentatricopeptide Repeat Containing (LRPPRC) controls CDK4/6i response in lung cancer by forming a feedback loop with CDK6. LRPPRC binds to CDK6-mRNA, increasing the stability and expression of CDK6. CDK6 and its downstream E2F Transcription Factor 1 (E2F1), bind to the LRPPRC promoter and elevate LRPPRC transcription. The activation of the LRPPRC-CDK6 loop facilitates cell cycle G1/S transition, oxidative phosphorylation, and cancer stem cell generation. Gossypol acetate (GAA), a gynecological medicine that has been repurposed as a degrader of LRPPRC, enhances the CDK4/6i sensitivity in vitro and in vivo. Our study reveals a mechanism responsible for CDK4/6i resistance and provides an enlightening approach to investigating the combinations of CDK4/6 and LRPPRC inhibitors in cancer therapy.

Date: 2023
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DOI: 10.1038/s41467-023-39854-y

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