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

Area of Science:

• Oncology
• Molecular Biology
• Cancer Therapeutics

Background:

• Cyclin Dependent Kinase 4 and 6 inhibitors (CDK4/6i) show promise in cancer treatment.
• Therapeutic efficacy of CDK4/6i is often limited by primary or acquired resistance across various tumor types.

Purpose of the Study:

• To elucidate the mechanism by which Leucine Rich Pentatricopeptide Repeat Containing (LRPPRC) influences response to CDK4/6 inhibitors in lung cancer.
• To investigate the potential of targeting the LRPPRC-CDK6 feedback loop for overcoming CDK4/6 inhibitor resistance.

Main Methods:

• Investigated the interaction between LRPPRC and CDK6-mRNA.
• Analyzed the binding of CDK6 and E2F Transcription Factor 1 (E2F1) to the LRPPRC promoter.
• Evaluated the effect of Gossypol acetate (GAA) on LRPPRC levels and CDK4/6i sensitivity in vitro and in vivo.

Main Results:

• Demonstrated that LRPPRC forms a positive feedback loop with CDK6, enhancing CDK6 mRNA stability and expression.
• Showed that CDK6 and E2F1 upregulate LRPPRC transcription, reinforcing the feedback loop.
• Confirmed that the LRPPRC-CDK6 loop promotes cell cycle progression, oxidative phosphorylation, and cancer stem cell generation.
• Established that Gossypol acetate (GAA), a LRPPRC degrader, sensitizes lung cancer cells to CDK4/6 inhibitors both in vitro and in vivo.

Conclusions:

• Identified a novel LRPPRC-CDK6 feedback loop as a key mechanism driving resistance to CDK4/6 inhibitors in lung cancer.
• Repurposed Gossypol acetate (GAA) as a potential therapeutic agent to overcome CDK4/6 inhibitor resistance.
• Proposed a combination strategy involving CDK4/6 and LRPPRC inhibitors for enhanced cancer therapy.