Clinical target promiscuity: lessons from ras molecular trials.
Mutated ras has been identified in approximately 30% of human tumors, and dysregulation of ras function and signal transduction pathways is a critical step in tumorigenesis. Herein, we review the early data that supports the concept that the intrinsic radiosensitivity of tumor cells can be altered by oncogenic ras expression and that this impacts the PI3K-dependent signaling cascade. This ras-induced radioresistance can be reversed using prenyl transferase inhibitors (PTIs.). We discuss the effects of PTIs as a radiosensitizer in both in vivo and in vitro studies and show that PTIs can lead to increased radiosensitization in vivo through a variety of potential mechanisms that enhance radiation-induced cell kill. We critically evaluate the use of ras biomarkers in predicting the clinical response to PTIs that may explain the mixed results seen thus far in clinical trials using PTIs as a clinical radiosensitizer. We conclude that Ras-mediated radioresistance is the result of multiple intercommunicating pathways functioning against a complex genetic background and a solitary biomarker may not be adequate to predict for PTI-mediated radiosensitization. Nonetheless, our knowledge of the ras-signaling pathway has led to development and testing of specific therapies directed against PI3K-AKT signaling pathways as a future approach towards clinical radiosensitization.
Rengan
Ramesh
R
Department of Radiation Oncology, University of Pennsylvania, 2-Donner, HUP, 3400 Spruce Street, Philadelphia, PA 19104, USA.
Cengel
Keith A
KA
Hahn
Stephen M
SM
D000818:Animals; D014408:Biomarkers, Tumor / Q000032:analysis* / Q000235:genetics; D002986:Clinical Trials as Topic; D004122:Dimethylallyltranstransferase / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D009154:Mutation; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000532:radiotherapy; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011836:Radiation Tolerance / Q000187:drug effects / Q000502:physiology*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
D014408:Biomarkers, Tumor; D004791:Enzyme Inhibitors; D011838:Radiation-Sensitizing Agents; D004122:Dimethylallyltranstransferase; D019869:Phosphatidylinositol 3-Kinases; D018631:ras Proteins