Abstract
Despite recent advances in oncology, diagnosis, and therapy, treatment of pancreatic ductal adenocarcinoma (PDAC) is still exceedingly challenging. PDAC remains the fourth leading cause of cancer-related deaths worldwide. Poor prognosis is due to the aggressive growth behavior with early invasion and distant metastasis, chemoresistance, and a current lack of adequate screening methods for early detection. Consequently, novel therapeutic approaches are urgently needed. Many hopes for cancer treatment have been placed in the death ligand tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) since it was reported to induce apoptosis selectively in tumor cells in vitro and in vivo. TRAIL triggers apoptosis through binding of the trans-membrane death receptors TRAIL receptor 1 (TRAIL-R1) also death receptor 4 (DR4) and TRAIL receptor 2 (TRAIL-R2) also death receptor 5 (DR5) thereby inducing the formation of the death-inducing signaling complex (DISC) and activation of the apoptotic cascade. Unlike chemotherapeutics, TRAIL was shown to be able to induce apoptosis in a p53-independent manner, making TRAIL a promising anticancer approach for p53-mutated tumors. These cancer-selective traits of TRAIL led to the development of TRAIL-R agonists, categorized into either recombinant variants of TRAIL or agonistic antibodies against TRAIL-R1 or TRAIL-R2. However, clinical trials making use of these agonists in various tumor entities including pancreatic cancer were disappointing so far. This is thought to be caused by TRAIL resistance of numerous primary tumor cells, an insufficient agonistic activity of the drug candidates tested, and a lack of suitable biomarkers for patient stratification. Nevertheless, recently gained knowledge on the biology of the TRAIL-TRAIL-R system might now provide the chance to overcome intrinsic or acquired resistance against TRAIL and TRAIL-R agonists. In this review, we summarize the status quo of clinical studies involving TRAIL-R agonists for the treatment of pancreatic cancer and critically discuss the suitability of utilizing the TRAIL-TRAIL-R system for successful treatment.
Highlights
Typical characteristics of cancers are self-sufficiency in growth signals, enhanced proliferative signaling, invasion, metastasis, angiogenesis, replicative immortality, and resistance to cell death [1,2].Pancreatic ductal adenocarcinoma (PDAC) harbors all of these classical hallmarks
Upon death-inducing signaling complex (DISC) formation, active caspase-8 cleaves Bcl-2 homologous antagonist domainkiller death agonist (Bid) generating truncated Bid, which translocates to mitochondria and eventually activates the mitochondrial cascade by triggering the oligomerization of the B cell lymphoma 2 (Bcl-2)-family members Bcl-2-associated X protein (Bax) and Bcl-2 homologous antagonist killer (Bak), resulting in mitochondrial outer membrane permeabilization (MOMP) [45,106]
These findings enabled the description of a pro-invasive character of endogenous TRAIL in Kirsten rat sarcoma viral oncogene homolog (KRAS)-mutated cells
Summary
Typical characteristics of cancers are self-sufficiency in growth signals, enhanced proliferative signaling, invasion, metastasis, angiogenesis, replicative immortality, and resistance to cell death [1,2]. Reduced response to conventional cytotoxic therapies is the culprit responsible for tumor development and progression despite therapy [3,4]. A less conventional therapeutic approach for PDAC arises from the stimulation of extrinsic apoptosis by death ligands. Appropriate expression of respective death receptors (DR) on the plasma membrane and a functional downstream signaling apparatus is required to successfully stimulate the extrinsic apoptosis cascade reviewed in [4,5,6]. Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL/Apo2L) and its pro-apoptotic receptors TRAIL receptor 1 (TRAIL-R1) and 2 (TRAIL-R2) represent such a death ligand/receptor system. The TRAIL-TRAIL-R system is expressed by PDAC cells and, on the other hand, capable of activating apoptosis selectively in tumor cells by binding to its death receptors reviewed in [7]
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