**14.1. Extrinsic apoptotic pathway**

*TRAIL*: This member of the TNF family stimulates the extrinsic apoptotic pathway in a wide variety of cancers upon binding to death receptors, while having no effect on normal cells. Therefore, the use of recombinant TRAIL or agonistic TRAIL-receptor antibodies constitutes a novel therapeutic strategy [172]. TRAIL has been found to bind five receptors in human cells: TRAIL-R1, TRAIL-R2, TRAIL-R3 (DcR1), TRAIL-R4 (DcR2) and the soluble receptor osteoprogeterin. However, DcR1 and DcR2 are unable to transduce a death signal and are considered "decoy receptors". Ashkenazi and colleagues have proposed that the specificity of TRAIL for cancer cells is due to the fact that normal cells express more frequently these decoy receptors [173]. Moreover, TRAIL only weakly induces the prosurvival NFkB pathway [78]. Unfortunately, many primary tumour cell lines have shown resistance to TRAIL [174]. It has been shown that in preclinical studies, the combination of recombinant human TRAIL (rhTRAIL, AMG951, Dulanermin) or agonistic antibodies with irradiation, several chemotherapeutic agents, Akt or proteosome inhibitors induced cell death in tumours resistant to TRAIL [175-177]. Therefore, the efficacy of rhTRAIL or anti-TRAIL-R1/2 antibodies is being examined in different phase I and phase II clinical trails alone or in combination with other chemotherapeutic agents [172,178,179].

*Fas activating compounds:* Fas, also called CD95 or APO-1 is a member of the TNF family of death receptors involved in the extrinsic apoptotic pathway. Fas plays an important role in regulation of the immune system. This receptor belongs to a subgroup within the TNFR family which includes TNFR1, DR3, TRAIL-R4 and TRAIL-R5 [180]. Fas has been recently implicated in the activation of RIP1, resulting in necroptosis when caspase-8 is inactive [181,182]. In addition, Tschopp and colleagues have demonstrated that Fas can activate other signalling pathways involved in proliferation or differentiation [109]. Fas agonists, such as highly aggregated FasL or anti-Fas antibodies are not suitable for cancer therapy owing to their profound liver toxicity. However, weaker Fas agonists may be useful. In this respect, APO010 is undergoing clinical trials for solid tumours [109].
