Molecular Mechanisms of Resistance to Anti-Angiogenic Drugs
Arianna Filippelli1, Valerio Ciccone1, Sandra Donnini1
1Department of Life Sciences, University of Siena, 53100 Siena, Italy.
Abstract:
The problem of drug resistance in cancer patients has been well in mind from the beginning of modern medicine and oncology treatments with the so called conventional cytotoxic therapy. With the advent of target therapy against tumor angiogenesis and in particular against the vascular endothelial growth factor (VEGF)/VEGF receptor system, researchers thought that resistance could be no more a problem, since the low pattern of proliferation displayed by endothelial cells. However, beside the efficacy demonstrated by antiangiogenic drugs, resistance during prolonged drug treatments appears as a limiting feature. Nowadays, various mechanisms of resistance to antiangiogenic therapeutics have been discovered, either innate and depending on the host, or acquired by the tumor cells, especially as a consequence of induced hypoxia by antiangiogenic drugs and the redundancy of proangiogenic factors in the tumor microenvironment, and other forms of tumor neovascularization, than sprouting angiogenesis. Here, we have reviewed the preclinical and clinical evidence for mechanisms of resistance to antiangiogenic drugs reported so far. The knowledge of the mechanisms underneath antiangiogenic drug resistance could be of help in the choice of the more appropriate drug, the development of novel therapeutic strategies, the design of proper drug combination protocols or new formulations of antiangiogenic strategies.
Insights
Cancer drug resistance remains a challenge, even with antiangiogenic therapies targeting vascular endothelial growth factor (VEGF). Understanding resistance mechanisms is key to developing new cancer treatments and drug combinations.
Area of Science:
- Oncology
- Cancer Biology
- Drug Resistance Mechanisms
Background:
- Drug resistance in cancer is a persistent challenge, initially observed with conventional cytotoxic therapies.
- The development of antiangiogenic drugs targeting the vascular endothelial growth factor (VEGF)/VEGF receptor system was expected to overcome resistance due to low endothelial cell proliferation.
- Despite initial efficacy, resistance to antiangiogenic drugs during prolonged treatment remains a significant clinical limitation.
Purpose of the Study:
- To review preclinical and clinical evidence of resistance mechanisms to antiangiogenic drugs.
- To consolidate current knowledge on how tumors develop resistance to therapies targeting angiogenesis.
- To provide insights for improving antiangiogenic therapeutic strategies.
Main Methods:
- Literature review of preclinical studies on antiangiogenic drug resistance.
- Analysis of clinical trial data related to resistance to antiangiogenic agents.
- Synthesis of evidence on innate and acquired resistance mechanisms.
Main Results:
- Resistance mechanisms are diverse, including innate host-dependent factors and acquired tumor cell adaptations.
- Acquired resistance is often linked to hypoxia induced by antiangiogenic drugs, promoting alternative proangiogenic pathways and tumor neovascularization beyond sprouting angiogenesis.
- Redundancy of proangiogenic factors in the tumor microenvironment contributes to therapeutic failure.
Conclusions:
- Understanding the mechanisms of antiangiogenic drug resistance is crucial for clinical practice.
- This knowledge can guide the selection of appropriate drugs, the development of novel therapeutic strategies, and the design of effective drug combinations or new formulations.
- Further research into resistance pathways will enhance the efficacy of antiangiogenic therapies in cancer treatment.
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