Inhibiting ras prenylation increases the radiosensitivity of human tumor cell lines with activating mutations of ras oncogenes

• Published in: Cancer research (Chicago, Ill.) Vol. 58; no. 8; pp. 1754 - 1761
• Main Authors: BERNHARD, E. J, MCKENNA, W. G, HAMILTON, A. D, SEBTI, S. M, YIMIN QIAN, JUNMIN WU, MUSCHEL, R. J
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.04.1998
• Subjects: Antineoplastic agents; Biological and medical sciences; Blotting, Western; Combined treatments (chemotherapy of immunotherapy associated with an other treatment); Dose-Response Relationship, Drug; Enzyme Inhibitors - pharmacology; Genes, ras - genetics; Humans; Medical sciences; Methionine - analogs & derivatives; Methionine - pharmacology; Mutation; Pharmacology. Drug treatments; Protein Prenylation - physiology; Proto-Oncogene Proteins p21(ras) - metabolism; Proto-Oncogene Proteins p21(ras) - physiology; Radiation therapy and radiosensitizing agent; Radiation Tolerance - drug effects; Radiation-Sensitizing Agents - pharmacology; Time Factors; Treatment with physical agents; Treatment. General aspects; Tumor Cells, Cultured; Tumors; Human; Enzyme; Transferases; Enzyme inhibitor; Malignant tumor; Radiotherapy; Resistance; Radiosensitizing agent; Radiosensitization; Dimethylallyltranstransferase; Established cell line; Combined treatment; Mutation; Onc gene; Tumor cell
• ISSN: 0008-5472; 1538-7445

The influence of activated ras oncogenes on the sensitivity of human tumor cells to killing by radiation has been an unresolved question in radiobiology. We have examined this question by measuring the radiation sensitivity of human tumor cell lines with oncogenic mutations in their H- or K-ras genes after treatment with prenyltransferase inhibitors that prevent the posttranslational modification of ras required for its activity. Using two measures of clonogenic survival, we have demonstrated radiosensitization in cell lines with oncogenic H-ras mutations or with oncogenic K-ras mutations when ras processing was inhibited by prenyltransferase inhibitor treatment. In contrast, the inhibition of ras processing in cell lines expressing wild-type ras had no effect on radiation-induced cell death. The prenyltransferase inhibitors themselves inhibited clonogenic survival in some cases, but this inhibition did not correlate with ras mutational status. Although treatment with prenyltransferase inhibitors and radiation resulted in a greater reduction 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 that the inhibition of oncogenic ras activity in human tumor cells can reduce the radiation survival of these cells, suggesting that oncogenic ras can contribute to radiation resistance in human tumors. These results further demonstrate the potential of using prenyltransferase inhibitors in combination with radiotherapy in the treatment of human malignancies.