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

Author:

Zhou Wei,Wang Wenxi,Liang Yuxin,Jiang Ruibin,Qiu Fensheng,Shao Xiying,Liu YangORCID,Fang LeORCID,Ni Maowei,Yu ChenhuanORCID,Zhao Yue,Huang Weijia,Li JiongORCID,Donovan Michael J.,Wang Lina,Ni Juan,Wang DachiORCID,Fu Ting,Feng Jianguo,Wang Xiaojia,Tan WeihongORCID,Fang XiaohongORCID

Abstract

AbstractKinase 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.

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary

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