- TRAIL can bind as a trimer to any of four membrane-bound and one soluble receptor, but only the two closely related cell surface death receptors TRAIL-R1 (DR4) and TRAIL-R2 (DR5) with intracellular functional death domains (DDs) that can induce apoptosis of tumor cells.3
- Trimerization of receptors leads to the formation of the death-inducing signaling complex (DISC).2,3
- DISC recruits and activates initiator caspases, triggering a series of downstream events that ultimately result in apoptotic cell death.2
IMPLICATIONS IN CANCER
TRAIL is an important immune effector molecule in the surveillance and elimination of developing tumors, therefore, inactivation of the TRAIL pathway and/or escape from TRAIL-mediated immunosurveillance might have an important role in tumor onset, progression, and treatment resisitance.4
Studies have demonstrated that TRAIL receptor agonists (TRAs) are generally well tolerated and that TRAIL can selectively trigger apoptosis in tumor cells across a wide range of tumor types, including colorectal cancer, lung cancer, pancreatic cancer, acute myeloid leukemia and non-Hodgkin lymphoma, without affecting normal cells.4-7,9
The induction of apoptosis can be divided into either intrinsic apoptosis, triggered by p53 in response to cellular injury, or extrinsic apoptosis induced upon death ligand binding to a death receptor; therefore, the ability of TRAIL agonism to induce apoptosis independently of p53 makes TRAIL a promising anticancer agent, especially in p53-mutated cancers.7,9 Furthermore, cancer cells can acquire resistance to TRAIL-induced apoptosis by loss of Bax or increased expression of BCL-2, BCL-XL, or MCL-1. (see BCL-2 Family Pathway section).5 Combinations of TRAs with BCL-2 pathway therapies, such as BCL-2 inhibitors, are being explored to circumvent potential TRA resistance.2,5
Solid Tumors and Hematologic Malignancies
Many tumor types show elevated and overexpressed intracellular levels of TRAIL-R1/R2, the receptors that bind the TRAIL ligand and form DISC which leads to apoptosis10
- Morgan-Lappe SE. ABBV-621: a best-in-class TRAIL-receptor agonist fusion protein that enhances optimal clustering for the treatment of solid and hematologic tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 April 1-5; Washington, DC.
- Tahir SK, Smith ML, Solomon LR, et al. Abbv-621 is a novel and potent TRAIL receptor agonist fusion protein that induces apoptosis alone and in combination with navitoclax and venetoclax in hematological tumors. Poster presented at: ASH 59th Annual Meeting & Exhibition; 2017 December 10; Atlanta, GA.
- Hymowitz SG, Christinger HW, Fuh G, et al. Triggering cell death: the crystal structure of Apo2L/ TRAIL in a complex with death receptor 5. Molecular Cell. 1999;4:563-571.
- Johnstone RW, Frew AJ, Smyth MJ. The TRAIL apoptotic pathway in cancer onset, progression and therapy. Nature Reviews. 2008;8:782-798.
- Lemke J, von Karstedt S, Zinngrebe J, Walczak H. Getting TRAIL back on track for cancer therapy. Cell Death and Differentiation. 2014;21:1350-1364.
- von Karstedt S, Montinaro A, Walczak H. Exploring the TRAILs less travelled: TRAIL in cancer biology and therapy. Nat Rev Cancer. 2017;17(6):352-366.
- Cassier PA, Castets M, Belhabri A, Vey N. Targeting apoptosis in acute myeloid leukaemia. Br J Cancer. 2017;117(8):1089-1098.
- Bolkun L, Lemancewicz D, Jablonska E, et al. The impact of TNF superfamily molecules on overall survival in acute myeloid leukaemia: correlation with biological and clinical features. Ann Hematol. 2015 Jan;94(1):35-43.
- Kretz AL, et al. TRAILBLAZING Strategies for Cancer Treatment. Cancers. 2019:11;456.
- Bertsh U, et al. Compartmentalization of TNF-related apoptosis-inducing ligand (TRAIL) death receptor functions: emerging role of nuclear TRAIL-R2. Cell Death & Disease. 2014:5;e1390.