Direct evidence for the contribution of activated N-ras and K-ras oncogenes to increased intrinsic radiation resistance in human tumor cell lines

Transformation with ras oncogenes results in increased radiation survival i n many but not all cells. In addition, prenyltransferase inhibitors, which inhibit ras proteins by blocking posttranslational modification, radiosensi tize cells with oncogenic ras, These findings suggest that oncogenic ras co ntributes to intrinsic radiation resistance. However, because introduction of ras oncogenes does not increase radiation survival in all cells and beca use prenyltransferase inhibitors target molecules other than ras, these stu dies left the conclusion that ras increases the intrinsic radiation resista nce of tumor cells in doubt. Here we show that genetic inactivation of K- o r N-ras oncogenes in human tumor cells (DLD-1 and HT1080, respectively) Lea ds to increased radiosensitivity, Reintroduction of the activated N-ras gen e into the HT1080 line, having Lost its mutant allele, resulted in increase d radiation resistance. This study lends further support to the hypothesis that expression of activated ras can contribute to intrinsic radiation resi stance in human tumor cells and extends this finding to the K- and N- membe rs of the ras family. These findings support the development of strategies that target ras for inactivation in the treatment of cancer.