ABSTRACT
Although the epidermal growth factor receptor (EGFR) signaling pathway is overactive in more than half of human cancers and mediates resistance to cytotoxic therapy, the molecular mechanisms of EGFR pathway-mediated resistance have remained elusive in cancer research. This difficulty partly stems from the lack of tissue models enabling clear separation of the many forms of cell death that the downstream signaling pathways of EGFR affect. We have created a model in Caenorhabditis elegans of radiation-induced reproductive cell death ("Radelegans") in isolation of all other forms of cell death. We have employed Radelegans to genetically define the role of the EGFR signaling pathway in protection from reproductive cell death, the primary form of tumor stem or clonogen cell death postirradiation. We have found that the RAS/mitogen-activated protein kinase (MAPK) downstream signal transduction pathway of EGFR is critical for protection from reproductive cell death in Radelegans. In addition, we have shown that RAS/MAPK pathway signaling is genetically linear with the DNA damage response pathway and acts downstream of the DNA damage checkpoint in the radioresponse, implicating this pathway in DNA repair post-cytotoxic therapy. These findings support the hypothesis that enhanced repair is a mechanism of RAS/MAPK pathway-mediated resistance to cytotoxic therapy through its interaction with the DNA damage response pathway postirradiation. We postulate that these findings also help explain why current treatment strategies, based on the presumption that tumors have ineffective repair compared with normal tissues, are ineffective in EGFR/RAS/MAPK pathway-mediated tumors. Radelegans is a platform to further define the genetic basis of the radiation response in tissues.