Signaling inhibition with radiation in colorectal cancer: clinical trials.
Ras has been shown to increase radiation resistance. Thus, upstream and downstream pathways from Ras could be targets for manipulation of radiosensitivity. Epidermal growth factor receptor (EGFR) expression and Akt phosphorylation are also associated with the response to radiation. A retrospective study evaluating EGFR and Akt in patients treated with multimodality therapy found a significant association between P-Akt and treatment failure. Moreover, these data are strengthened by in vitro studies showing that inhibition of EGFR, Ras, PI3K, and Akt radiosensitized cancer cell lines. We have previously shown that PI3K is a mediator of Ras-induced radiation resistance. We now suggest that EGFR, which is upstream of PI3K, may also mediate resistance through a common pathway. In addition to EGFR and Ras, PTEN can also regulate the PI3K pathway. Identifying a common signal for EGFR, Ras, or PTEN that results in radiation resistance may uncover targets for developing molecular-based radiosensitization protocols for tumors resistant to radiation and thus improve local control.
McKenna
W Gillies
WG
Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA 19004, USA.
Muschel
Ruth J
RJ
Gupta
Anjali
A
Hahn
Stephen
S
Bernhard
Eric J
EJ
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D002986:Clinical Trials as Topic; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000532:radiotherapy*; D004122:Dimethylallyltranstransferase / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D066246:ErbB Receptors / Q000378:metabolism; D051231:Farnesyltranstransferase; D006801:Humans; D051059:PTEN Phosphohydrolase; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D011836:Radiation Tolerance; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D015398:Signal Transduction; D017211:Treatment Failure; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D018631:ras Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*
D004791:Enzyme Inhibitors; D011518:Proto-Oncogene Proteins; D011838:Radiation-Sensitizing Agents; D025521:Tumor Suppressor Proteins; D019883:Alkyl and Aryl Transferases; D004122:Dimethylallyltranstransferase; D051231:Farnesyltranstransferase; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D010744:Phosphoric Monoester Hydrolases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D018631:ras Proteins