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Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF family that signals through two receptors, DR4 and DR5, providing a potential target for therapeutic intervention. Here we show that two point mutations in DR5 (E338K and L334F), which were identified in cancer patients, inhibit its ability to recruit the adaptor protein FADD. Cells expressing mutant versions of DR5 but wildtype versions of DR4 are resistant to some TRAIL pathway agonists indicating that the mutant DR5 can inhibit signaling through DR4 for some, but not all, activators of the pathway. Specifically, we found that cells expressing mutant DR5 receptors are resistant to apoptosis induced by therapeutic anti-DR5 antibodies but are sensitive to therapeutic anti-DR4 antibodies and retain sensitivity to some (not all) preparations of recombinant TRAIL. The mutant cells differ in their ability to activate downstream MAPK, p38 and NFκB signaling indicating that the mutations have different effects on some signaling pathways compared with others. These data show that different TRAIL pathway activators work by different mechanisms and may therefore provide a basis to choose specific activators of the TRAIL pathway to tailor treatments for particular patients.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]