The potential of death receptor 4- and 5-directed therapies in the treatment of lung cancer.

Aberrations of the intracellular apoptotic balance--reducing proapoptotic signaling and increasing antiapoptotic signaling--are common in cancer cells. Increasing apoptosis through the direct manipulation of the apoptotic machinery offers novel anticancer strategies. Of the 2 main interacting proapoptotic pathways, the extrinsic pathway is characterized by ligand dependent stimulation of cell surface death receptor (DRs). Recombinant ligand and agonistic monoclonal antibodies directed against the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptors, DR 4 (TRAIL-R1) and/or DR 5 (TRAIL-R2), are now being explored within clinical trials. These agents appear well tolerated with hints of single-agent activity in lymphoma, colorectal cancer, chondrosarcoma, and non-small-cell lung cancer. Numerous molecular factors influencing sensitivity or resistance have been identified in vitro, but the determinants of clinical benefit remain unclear. Preclinically, synergy with cytotoxic chemotherapy and radiation therapy is well documented, with DR4/5 stimulation helping to tip the intracellular processing of multiple stimuli in favor of cell death. Provided that a wide therapeutic margin relative to normal cells can be maintained, maximizing apoptotic responses to standard treatments through DR4/5-directed therapy, with or without additional blockade of antiapoptotic signaling, has considerable potential in the treatment of lung cancer. Trials of DR4/5-directed therapies in combination with standard first-line chemotherapy for non-small-cell lung cancer are under way.