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Tyro3 Targeting as a Radiosensitizing Strategy in Bladder Cancer through Cell Cycle Dysregulation
Linda Silina1,2,3, Florent Dufour1, Audrey Rapinat4
1Institut Curie, CNRS, UMR144, Equipe Labellisée Ligue Contre le Cancer, PSL Research University, 75005 Paris, France.
Abstract:
Bladder cancer is a common cancer; it is the tenth most common cancer in the world. Around one fourth of all diagnosed patients have muscle-invasive bladder cancer (MIBC), characterized by advanced tumors and which remains a lethal disease. The standard treatment for MIBC is the bladder removal by surgery. However, bladder-preserving alternatives are emerging by combining chemotherapy, radiotherapy and minimal surgery, aiming to increase the patient's quality of life. The aim of the study was to improve these treatments by investigating a novel approach where in addition to radiotherapy, a receptor, TYRO3, a member of TAM receptor tyrosine kinase family known to be highly expressed on the bladder cancer cells and involved in the control of cell survival is targeted. For this, we evaluated the influence of TYRO3 expression levels on a colony or cell survival assays, DNA damage, γH2AX foci formation, gene expression profiling and cell cycle regulation, after radiation on different bladder cell models. We found that TYRO3 expression impacts the radiation response via the cell cycle dysregulation with noeffets on the DNA repair. Therefore, targeting TYRO3 is a promising sensitization marker that could be clinically employed in future treatments.
Insights
Targeting the TYRO3 receptor in bladder cancer cells enhances radiotherapy effectiveness. This approach impacts cell cycle regulation, offering a promising strategy for improving bladder cancer treatment outcomes.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Bladder cancer is a prevalent malignancy, with muscle-invasive bladder cancer (MIBC) representing a significant portion of cases and posing a lethal threat.
- Current standard treatment for MIBC involves radical cystectomy, but bladder-preserving strategies combining chemotherapy, radiotherapy, and minimal surgery are being explored to improve patient quality of life.
Purpose of the Study:
- To investigate the potential of targeting the TYRO3 receptor, a TAM receptor tyrosine kinase family member highly expressed in bladder cancer cells, to enhance radiotherapy efficacy.
- To evaluate the impact of TYRO3 expression on bladder cancer cell response to radiation, including survival, DNA damage, and cell cycle regulation.
Main Methods:
- Utilized various bladder cancer cell models to assess the influence of TYRO3 expression levels.
- Conducted colony and cell survival assays, DNA damage assessments (including γH2AX foci formation), gene expression profiling, and cell cycle analysis following radiation exposure.
Main Results:
- Found that TYRO3 expression significantly impacts the response of bladder cancer cells to radiotherapy.
- Demonstrated that TYRO3 influences radiation response primarily through dysregulation of the cell cycle.
- Observed no significant effect of TYRO3 expression on DNA repair mechanisms.
Conclusions:
- Targeting TYRO3 in conjunction with radiotherapy shows promise as a strategy to sensitize bladder cancer cells.
- TYRO3 may serve as a valuable biomarker for predicting response to combined radiation and TYRO3-targeting therapies.
- This approach holds potential for clinical application in improving bladder cancer treatment outcomes.
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