Inhibition of Eukaryotic Initiating Factor eIF4E Overcomes Abemaciclib Resistance in Gastric Cancer
Huo-Long Zha1, Wei Chen2, Wei Shi3
1Department of Gastroenterology, Renmin Hospital, Hubei University of Medicine, Shiyan, 442000, China.
Objective:
Aberrant activating mutations in cyclin-dependent kinases 4 and 6 (CDK4/6) are common in various cancers, including gastroesophageal malignancies. Although CDK4/6 inhibitors, such as abemaciclib and palbociclib, have been approved for breast cancer treatment, their effectiveness as a monotherapy remains limited for gastroesophageal tumors. The present study explored the underlying mechanism of abemaciclib resistance.
Methods:
Abemaciclib-resistant gastric cancer cell lines were generated, and the phospho-eukaryotic translation initiation factor 4E (p-eIF4E) and eIF4E expression was compared between resistant and parental cell lines. In order to analyze the role of eIF4E in cell resistance, siRNA knockdown was employed. The effectiveness of ribavirin alone and its combination with abemaciclib was evaluated in the gastric cancer xenograft mouse model.
Results:
The upregulation of eIF4E was a common feature in gastric cancer cells exposed to prolonged abemaciclib treatment. Gastric cancer cells with increased eIF4E levels exhibited a better response to eIF4E inhibition, especially those that were resistant to abemaciclib. Ribavirin, which is an approved anti-viral drug, significantly improved the efficacy of abemaciclib, both in vitro and in vivo, by inhibiting eIF4E. Importantly, ribavirin effectively suppressed the abemaciclib-resistant gastric cancer growth in mice without causing toxicity.
Conclusion:
These findings suggest that targeting eIF4E can enhance the abemaciclib treatment for gastric cancer, proposing the potential combination therapy of CDK4/6 inhibitors with ribavirin for advanced gastric cancer.
Insights
Targeting eukaryotic translation initiation factor 4E (eIF4E) with ribavirin overcomes abemaciclib resistance in gastric cancer. This combination therapy shows promise for treating advanced gastric cancer by inhibiting eIF4E and suppressing tumor growth without toxicity.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Aberrant cyclin-dependent kinases 4 and 6 (CDK4/6) mutations are prevalent in gastroesophageal cancers.
- CDK4/6 inhibitors like abemaciclib show limited efficacy as monotherapy for these tumors.
- Understanding abemaciclib resistance mechanisms is crucial for improving treatment outcomes.
Purpose of the Study:
- To investigate the mechanism underlying abemaciclib resistance in gastric cancer.
- To evaluate the therapeutic potential of targeting eukaryotic translation initiation factor 4E (eIF4E) in overcoming this resistance.
- To assess the efficacy of combining abemaciclib with ribavirin, an eIF4E inhibitor.
Main Methods:
- Generated abemaciclib-resistant gastric cancer cell lines.
- Assessed expression of phospho-eukaryotic translation initiation factor 4E (p-eIF4E) and eIF4E.
- Utilized siRNA knockdown to analyze eIF4E's role in resistance.
- Evaluated ribavirin and abemaciclib combination therapy in gastric cancer xenograft models.
Main Results:
- Upregulation of eIF4E was observed in gastric cancer cells resistant to abemaciclib.
- Increased eIF4E levels correlated with enhanced response to eIF4E inhibition, particularly in resistant cells.
- Ribavirin significantly enhanced abemaciclib efficacy in vitro and in vivo by inhibiting eIF4E.
- Ribavirin effectively suppressed abemaciclib-resistant gastric cancer growth in mice without observed toxicity.
Conclusions:
- Targeting eIF4E is a viable strategy to enhance abemaciclib treatment efficacy in gastric cancer.
- Combination therapy with CDK4/6 inhibitors and ribavirin holds potential for treating advanced gastric cancer.
- This approach offers a promising strategy to overcome abemaciclib resistance in gastroesophageal malignancies.
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