Identification of kinases activated by multiple pro-angiogenic growth factors
Scott Gruver1, Scott Rata1, Leonid Peshkin1
1Department of Systems Biology, Harvard University Medical School, Boston, MA, United States.
Abstract:
Antiangiogenic therapy began as an effort to inhibit VEGF signaling, which was thought to be the sole factor driving tumor angiogenesis. It has become clear that there are more pro-angiogenic growth factors that can substitute for VEGF during tumor vascularization. This has led to the development of multi-kinase inhibitors which simultaneously target multiple growth factor receptors. These inhibitors perform better than monotherapies yet to date no multi-kinase inhibitor targets all receptors known to be involved in pro-angiogenic signaling and resistance inevitably occurs. Given the large number of pro-angiogenic growth factors identified, it may be impossible to simultaneously target all pro-angiogenic growth factor receptors. Here we search for kinase targets, some which may be intracellularly localized, that are critical in endothelial cell proliferation irrespective of the growth factor used. We develop a quantitative endothelial cell proliferation assay and combine it with "kinome regression" or KIR, a recently developed method capable of identifying kinases that influence a quantitative phenotype. We report the kinases implicated by KIR and provide orthogonal evidence of their importance in endothelial cell proliferation. Our approach may point to a new strategy to develop a more complete anti-angiogenic blockade.
Insights
Researchers identified novel kinase targets critical for cancer cell proliferation, independent of growth factors. This discovery may lead to more effective anti-angiogenic therapies by blocking tumor vascularization pathways.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Antiangiogenic therapy initially focused on inhibiting VEGF, but tumors develop resistance via alternative pro-angiogenic factors.
- Multi-kinase inhibitors offer improved efficacy over monotherapies but do not target all relevant receptors, leading to inevitable resistance.
- Targeting all pro-angiogenic growth factor receptors may be unfeasible due to their large number.
Purpose of the Study:
- To identify novel kinase targets essential for endothelial cell proliferation, irrespective of the specific growth factor.
- To explore intracellular kinases that play a critical role in tumor vascularization.
- To develop a more comprehensive anti-angiogenic blockade strategy.
Main Methods:
- Development of a quantitative endothelial cell proliferation assay.
- Application of kinome regression (KIR), a method to identify kinases influencing quantitative phenotypes.
- Orthogonal validation of identified kinase targets in endothelial cell proliferation.
Main Results:
- Identification of specific kinases critical for endothelial cell proliferation using KIR.
- Confirmation of the importance of these kinases through orthogonal experimental evidence.
- The identified kinases are crucial for tumor vascularization regardless of the initiating growth factor.
Conclusions:
- A novel strategy using kinome regression can identify key kinases regulating endothelial cell proliferation.
- This approach may overcome resistance mechanisms seen with current anti-angiogenic therapies.
- Targeting these newly identified kinases could lead to a more complete anti-angiogenic blockade.
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