Abemaciclib sensitizes HPV-negative cervical cancer to chemotherapy via specifically suppressing CDK4/6-Rb-E2F and mTOR pathways.

Abstract

Cervical cancer is the second most common malignancy in women, and the novel therapeutic treatment is needed. Abemaciclib is a FDA-approved drug for breast cancer treatment. In this work, we identified that abemaciclib has potent anti-cervical cancer activity. We demonstrate that abemaciclib is the most effective drug against human papillomavirus (HPV)-negative cervical cancer cells compared to ribociclib and palbociclib, with its IC50 at nanomolar concentration range. This is achieved by the inhibition of proliferation and induction of apoptosis, through specifically suppressing CDK4/6-Rb-E2F and mTOR pathways by abemaciclib in HPV-negative cervical cancer cells. Of note, the combination of abemaciclib with paclitaxel and cisplatin at sublethal concentration results in much greater efficacy than chemotherapy alone. In addition, we confirm the efficacy of abemaciclib and its combination with paclitaxel or cisplatin at the doses that are not toxic to mice in HPV-negative cervical cancer xenograft mouse model. Interestingly, we show that abemaciclib and other CDK4/6 inhibitors are not effective in targeting HPV-positive cervical cancer cells, and this is likely to be associated with the high p16 and low Rb expression in HPV-positive cervical cancer cells. Our work is the first to provide the preclinical evidence to demonstrate the potential of abemaciclib for the treatment of HPV-negative cervical cancer. The mechanism analysis highlights the therapeutic value of inhibiting CDK4/6 in HPV-negative but not HPV-positive cervical cancer.

• Authors: Yuan Liu, Runsheng Zhao, Shanshan Fang, Quan Li, Yiqiang Jin, Bo Liu
• Journal: Fundamental & clinical pharmacology (Fundam Clin Pharmacol) Vol. 35 Issue 1 Pg. 156-164 (Feb 2021) ISSN: 1472-8206 [Electronic] England
• PMID: 32446293 (Publication Type: Journal Article)
• Copyright: © 2020 Société Française de Pharmacologie et de Thérapeutique.

Chemical References

• Aminopyridines
• Benzimidazoles
• E2F Transcription Factors
• Retinoblastoma Protein
• abemaciclib
• MTOR protein, human
• TOR Serine-Threonine Kinases
• CDK4 protein, human
• CDK6 protein, human
• Cyclin-Dependent Kinase 4
• Cyclin-Dependent Kinase 6

Topics

• Alphapapillomavirus (isolation & purification)
• Aminopyridines (pharmacology)
• Animals
• Benzimidazoles (pharmacology)
• Cell Line, Tumor
• Cyclin-Dependent Kinase 4 (antagonists & inhibitors)
• Cyclin-Dependent Kinase 6 (antagonists & inhibitors)
• E2F Transcription Factors (antagonists & inhibitors)
• Female
• Humans
• Mice
• Retinoblastoma Protein (antagonists & inhibitors)
• TOR Serine-Threonine Kinases (antagonists & inhibitors)
• Uterine Cervical Neoplasms (drug therapy, virology)
• Xenograft Model Antitumor Assays