Targeting apoptosis extracellularly
The extrinsic pathway has been a target in drug development. One class of agents consists of pro-apoptotic receptor agonists (PARAs).35 Pro-apoptotic receptors are ubiquitously expressed in cancers and activate caspases in a p53-independent manner.35 In conjunction, prevalent oncogenes such as Myc or Ras appear to increase tumor sensitivity to the extrinsic pathway, giving PARAs therapeutic potential.35 Of the pro-apoptotic receptors that control this signaling pathway, DR4 and DR5 are particularly attractive targets for agonistic drugs because they are broadly expressed in multiple cancers and appear to be better primed for stimulation when expressed on malignant vs normal cells.35 Two classes of PARAs that target DR4 and/or DR5 have been developed: recombinant human (rh) Apo2L/TRAIL (Figure 3.2), which activates both receptors; and monoclonal agonistic antibodies (Figure 3.2), which specifically activate only DR4 or DR5.35 These molecules bind to their respective receptors and trigger activation of the extrinsic apoptotic pathway. In many cancer cells, this also leads to activation of the intrinsic pathway—activated caspase 8 cleaves and activates Bid, eventually leading to mitochondrial engagement, caspase activation, and apoptosis.35
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Figure 3.2. PARAs target death receptors to induce apoptosis of cancer cells.
Adapted from Ashkenazi 2002.28 Reproduced with permission from Nat Rev Cancer.