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Kinase profiling of liposarcomas using RNAi and drug screening assays identified druggable targets
Deepika Kanojia1, Manoj Garg2, Jacqueline Martinez3
1Cancer Science Institute of Singapore, National University of Singapore, Singapore, 117599, Singapore. csidk@nus.edu.sg.
Background:
Liposarcoma, the most common soft tissue tumor, is understudied cancer, and limited progress has been made in the treatment of metastatic disease. The Achilles heel of cancer often is their kinases that are excellent therapeutic targets. However, very limited knowledge exists of therapeutic critical kinase targets in liposarcoma that could be potentially used in disease management.
Methods:
Large RNAi and small-molecule tyrosine kinase inhibitor screens were performed against the proliferative capacity of liposarcoma cell lines of different subtypes. Each small molecule inhibitor was either FDA approved or in a clinical trial.
Results:
Screening assays identified several previously unrecognized targets including PTK2 and KIT in liposarcoma. We also observed that ponatinib, multi-targeted tyrosine kinase inhibitor, was the most effective drug with anti-growth effects against all cell lines. In vitro assays showed that ponatinib inhibited the clonogenic proliferation of liposarcoma, and this anti-growth effect was associated with apoptosis and cell cycle arrest at the G0/G1 phase as well as a decrease in the KIT signaling pathway. In addition, ponatinib inhibited in vivo growth of liposarcoma in a xenograft model.
Conclusions:
Two large-scale kinase screenings identified novel liposarcoma targets and a FDA-approved inhibitor, ponatinib with clear anti-liposarcoma activity highlighting its potential therapy for treatment of this deadly tumor.
Insights
Researchers identified novel kinase targets in liposarcoma, a common soft tissue cancer. The FDA-approved drug ponatinib demonstrated significant anti-cancer effects, offering potential new treatment options.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Liposarcoma is the most common soft tissue tumor but remains understudied, with limited therapeutic options for metastatic disease.
- Kinases are critical targets in cancer therapy, yet specific therapeutic targets in liposarcoma are not well-defined.
Purpose of the Study:
- To identify critical kinase targets and effective therapeutic agents for liposarcoma.
- To evaluate the efficacy of small-molecule tyrosine kinase inhibitors against liposarcoma cell lines.
Main Methods:
- Conducted large-scale RNAi and small-molecule tyrosine kinase inhibitor screens against liposarcoma cell lines.
- Utilized FDA-approved or clinically trialed small molecule inhibitors.
Main Results:
- Identified PTK2 and KIT as novel targets in liposarcoma.
- Ponatinib, a multi-targeted tyrosine kinase inhibitor, exhibited the most potent anti-proliferative effects across all tested liposarcoma subtypes.
- Ponatinib induced apoptosis, G0/G1 cell cycle arrest, and inhibited the KIT signaling pathway in vitro, and suppressed tumor growth in a xenograft model.
Conclusions:
- Kinase screenings revealed novel therapeutic targets for liposarcoma.
- Ponatinib demonstrates significant anti-liposarcoma activity, highlighting its potential as a therapeutic agent for this malignancy.
