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**1. Introduction** 

**10** 

*Italy* 

**Signalling Pathways** 

Roberta Di Pietro *G. d'Annunzio University* 

**Leading to TRAIL Resistance** 

*Department of Medicine and Aging Sciences, Chieti* 

One fundamental problem of most malignancies, including those of haematological origin, is the development of multiple mechanisms of resistance, which progressively reduce or suppress the therapeutic efficacy of conventional radio-chemotherapy. In recent years novel compounds have been identified to overcome this major hurdle. Among these, TNF-related apoptosis-inducing ligand (TRAIL) generated considerable enthusiasm for its anticancer therapeutic effectiveness, selectively targeted to a wide range of cancer cells without affecting cells derived from normal tissues and organs. A number of preliminary studies sustain the use of TRAIL-Receptors agonistic antibodies (TRAs) instead of rTRAIL (recombinant TRAIL) in the treatment of tumour cells protected from rTRAIL-induced apoptosis by the expression of cell surface decoy receptors. Although the early clinical trials are promising and well tolerated, the efficacy of these novel approaches is restricted to patients with TRAIL-sensitive tumours. In addition, TRAIL-Rs loss or mutations that can often occur in neoplastic diseases can compromise expected therapeutic results. To overcome TRAIL resistance, novel strategies based on the combination of TRAIL with radiochemotherapy, or with proteasome or histone deacetylase or NF-B inhibitors have been developed. In light of this complex background, this chapter will discuss the current knowledge of the signalling pathways leading to TRAIL resistance and promising targeted

**2. The TRAIL/TRAIL-Rs system as a novel avenue in anticancer treatment** 

In recent years novel compounds have been identified to overcome emergence of cancer cells resistance to conventional radio-chemotherapy. Among these, TRAIL generated considerable enthusiasm for its anticancer therapeutic effectiveness, selectively targeted to a wide range of cancer cells without affecting cells derived from normal tissues and organs. TRAIL, also known as Apo-2 Ligand (Apo-2L) (Pitti et al., 1996), is a member of the TNF super-family of cytokines including structurally related proteins that play important roles in regulating cell death, immune response and inflammation. The story of TRAIL begins when a new member of the TNF super-family capable of inducing apoptosis was identified and characterized by virtue of its sequence homology to CD95/Fas/Apo1L (FasL) and TNF (Wiley et al., 1995).

therapies in the treatment of haematological malignancies.

