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

CDK4/6 inhibition is a promising therapeutic approach to treat cancer, but it is challenged by resistance development. Here, the authors show that the RNA binding protein LRPPRC forms a positive feedback loop with CDK6 and inhibiting LRPPRC with the FDA-approved gossypol acetate overcomes CDK4/6 inhibition resistance. 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.

Automated summary

The study reveals that the RNA binding protein LRPPRC forms a positive feedback loop with CDK6, and inhibiting LRPPRC overcomes CDK4/6 inhibition resistance. This research uncovers the mechanism of CDK4/6i resistance and provides a novel approach to combine CDK4/6 and LRPPRC inhibitors for cancer therapy.