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Abemaciclib sensitizes HPV-negative cervical cancer to chemotherapy via specifically suppressing CDK4/6-Rb-E2F and
Yuan Liu1, Runsheng Zhao1, Shanshan Fang1
1Department of Oncology, Xiangyang Central Hospital, Hubei University of Arts and Science, No.136, Jingzhou Road, Xiangyang, 441000, China.
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.
Insights
Abemaciclib shows potent anti-cervical cancer activity, particularly in human papillomavirus (HPV)-negative cells, by inhibiting proliferation and inducing apoptosis. This CDK4/6 inhibitor offers a promising new therapeutic strategy for HPV-negative cervical cancer.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Cervical cancer remains a significant global health challenge, necessitating novel therapeutic approaches.
- Abemaciclib, a cyclin-dependent kinase (CDK) 4/6 inhibitor, is approved for breast cancer but its efficacy in cervical cancer is unexplored.
- Human papillomavirus (HPV) status is a critical factor in cervical cancer development and potential treatment response.
Purpose of the Study:
- To investigate the anti-cervical cancer activity of abemaciclib, a CDK4/6 inhibitor.
- To compare the efficacy of abemaciclib with other CDK4/6 inhibitors (ribociclib, palbociclib) in HPV-negative and HPV-positive cervical cancer cells.
- To elucidate the underlying molecular mechanisms of abemaciclib's action and its potential in combination therapy.
Main Methods:
- In vitro studies using human cervical cancer cell lines (HPV-negative and HPV-positive).
- In vivo studies using a cervical cancer xenograft mouse model.
- Assessment of cell proliferation, apoptosis, and Western blot analysis to evaluate pathway suppression (CDK4/6-Rb-E2F, mTOR).
- Combination therapy studies with paclitaxel and cisplatin.
Main Results:
- Abemaciclib demonstrated potent anti-proliferative and pro-apoptotic effects in HPV-negative cervical cancer cells at nanomolar concentrations, outperforming ribociclib and palbociclib.
- Abemaciclib effectively suppressed the CDK4/6-Rb-E2F and mTOR pathways in HPV-negative cells.
- Combination therapy with abemaciclib and chemotherapy (paclitaxel, cisplatin) showed significantly enhanced efficacy in vitro and in vivo.
- Abemaciclib showed no significant efficacy in HPV-positive cervical cancer cells, likely due to high p16 and low Rb expression.
Conclusions:
- Abemaciclib exhibits significant preclinical efficacy against HPV-negative cervical cancer through specific pathway inhibition.
- Combination therapy with abemaciclib and standard chemotherapeutics presents a promising strategy for HPV-negative cervical cancer treatment.
- The differential efficacy of abemaciclib based on HPV status highlights the importance of molecular stratification in cervical cancer therapy.
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