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Signaling inhibition with radiation in colorectal cancer: clinical trials
W Gillies McKenna1, Ruth J Muschel, Anjali Gupta
1Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA 19004, USA.
Abstract:
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.
Insights
Ras signaling pathways increase cancer radiation resistance. Targeting epidermal growth factor receptor (EGFR) and Akt may improve radiosensitivity and treatment outcomes for radiation-resistant tumors.
Area of Science:
- Oncology
- Molecular Biology
- Radiation Oncology
Background:
- Ras proteins are known to confer resistance to radiation therapy.
- Epidermal growth factor receptor (EGFR) and Akt signaling pathways are implicated in radiation response.
- Previous studies link PI3K to Ras-mediated radiation resistance.
Purpose of the Study:
- To investigate the role of EGFR and other upstream regulators in radiation resistance.
- To identify common signaling pathways mediating resistance to radiation therapy.
- To explore potential molecular targets for radiosensitization protocols.
Main Methods:
- Retrospective analysis of EGFR and phosphorylated Akt (P-Akt) in patients undergoing multimodality therapy.
- In vitro studies assessing the radiosensitizing effects of inhibiting EGFR, Ras, PI3K, and Akt.
- Evaluation of the PI3K pathway as a mediator of Ras-induced radiation resistance.
Main Results:
- A significant association was found between P-Akt levels and treatment failure in patients.
- Inhibition of EGFR, Ras, PI3K, and Akt demonstrated radiosensitizing effects on cancer cell lines.
- EGFR is suggested as a potential mediator of resistance, acting upstream of PI3K.
Conclusions:
- EGFR, Ras, and PTEN are key regulators of the PI3K pathway, influencing radiation resistance.
- Targeting these common signaling molecules may lead to novel radiosensitization strategies.
- Developing molecular-based protocols could improve local control for radiation-resistant tumors.
