Mutations at the H-, N- and K-ras loci are among the most frequent genetic alterations in human
cancers. In this study, we have investigated the effect of
AZD3409, a novel,
peptidomimetic prenyltransferase inhibitor (PTI), on the radiosensitivity of cells with mutated ras alleles.
AZD3409, developed by AstraZeneca, inhibits both farnesyl- and geranylgeranyl
transferase in cell free systems.
AZD3409 inhibits the growth of a variety of human
cancer cell lines, including cells that express mutant alleles of either K- or H- ras and was well tolerated when administered orally to healthy volunteers in a phase I clinical trial. We have previously shown that PTI can radiosensitize human and rodent
cancer cell lines that express activated RAS. Here we assessed the ability of
AZD3409 to radiosensitize human
cancer cell lines in vivo and in vitro and the activation state of
RAS proteins in treated cells. Once daily
oral administration of
AZD3409 to nude mice bearing PSN-1 and MiaPaCa-2 human
pancreatic cancer xenografts expressing mutant K-ras was well tolerated and resulted in a supra-additive reduction in clonogenic cell survival after irradiation. Similarly,
AZD3409 reduced clonogenic survival in cells that express either mutant K- or H- ras in vitro. We next examined the effect of
AZD3409 on the processing and activation of K- and H-RAS. AZD3409-mediated radiosensitization, both in vivo and in vitro, correlates with a decrease in H-RAS processing without detectable effect on K-RAS processing. RAS activation assays show that the decreased H-RAS processing is accompanied by decreased H-RAS activation in cell lines with mutations in either K- or H-ras. However, no decrease in K-RAS activation was detected. Thus, radiosensitization of human
cancer cells that express mutated K-RAS occurred under conditions where
AZD3409 inihibits the activation of farneyslated H-RAS, but did not inhibit K-RAS activation.