INHIBITING RAS PRENYLATION INCREASES THE RADIOSENSITIVITY OF HUMAN TUMOR-CELL LINES WITH ACTIVATING MUTATIONS OF RAS ONCOGENES

The influence of activated ras oncogenes on the sensitivity of human t umor cells to killing by radiation has been an unresolved question in radiobiology, We have examined this question by measuring the radiatio n sensitivity of human tumor cell lines with oncogenic mutations in th eir H-or K-ras genes after treatment with prenyltransferase inhibitors that prevent the posttranslational modification of ras required for i ts activity. Using two measures of clonogenic survival, we have demons trated radiosensitization in cell lines with oncogenic H-ras mutations or with oncogenic K-ras mutations when ras processing was inhibited b y prenyltransferase inhibitor treatment, In contrast, the inhibition o f ras processing in cell lines expressing wild-type ras had no effect on radiation-induced cell death. The prenyltransferase inhibitors them selves inhibited clonogenic survival in some cases, but this inhibitio n did not correlate with ras mutational status. Although treatment wit h prenyltransferase inhibitors and radiation resulted in a greater red uction of clonogenicity than either treatment alone in cells with wild -type ras, treatment with both agents had a synergistic effect on cell killing in tumor cells with ras mutations. Our results demonstrate th at the inhibition of oncogenic ras activity in human tumor cells can r educe the radiation survival of these cells, suggesting that oncogenic ras can contribute to radiation resistance in human tumors. These res ults further demonstrate the potential of using prenyltransferase inhi bitors in combination with radiotherapy in the treatment of human mali gnancies.