Clinical target promiscuity: lessons from ras molecular trials
Ramesh Rengan1, Keith A Cengel, Stephen M Hahn
1Department of Radiation Oncology, University of Pennsylvania, 2-Donner, HUP, 3400 Spruce Street, Philadelphia, PA 19104, USA.
Cancer Metastasis Reviews
|May 8, 2008
Summary
Oncogenic Ras expression can cause tumor cells to resist radiation therapy. Prenyl transferase inhibitors (PTIs) can reverse this radioresistance, enhancing radiation
Area of Science:
- Oncology
- Molecular Biology
- Radiotherapy
Background:
- Mutated Ras is implicated in ~30% of human tumors, with its dysregulation being critical in tumorigenesis.
- Oncogenic Ras expression alters tumor cell radiosensitivity, impacting PI3K-dependent signaling.
- Ras-mediated radioresistance presents a challenge in cancer treatment.
Purpose of the Study:
- To review early data on oncogenic Ras expression affecting tumor cell radiosensitivity.
- To discuss the role of prenyl transferase inhibitors (PTIs) in overcoming Ras-induced radioresistance.
- To evaluate the predictive value of Ras biomarkers for clinical response to PTIs.
Main Methods:
- Review of existing in vivo and in vitro studies on PTIs as radiosensitizers.
- Analysis of mechanisms by which PTIs enhance radiation-induced cell kill.
- Critical evaluation of Ras biomarkers in predicting clinical outcomes of PTI therapy.
Main Results:
- Oncogenic Ras expression confers radioresistance, which can be reversed by PTIs.
- PTIs demonstrate radiosensitizing effects in both in vitro and in vivo models.
- Potential mechanisms for PTI-mediated radiosensitization involve enhancing radiation-induced cell kill.
Conclusions:
- Ras-mediated radioresistance involves complex, interconnected pathways and a multifaceted genetic background.
- A single Ras biomarker may be insufficient for predicting clinical response to PTIs.
- Targeting PI3K-AKT signaling pathways represents a promising future strategy for clinical radiosensitization.
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