Trail

Overview

  • TNF-related apoptosis inducing ligand (TRAIL) is a member of the TNF superfamily of proteins involved in activating several intracellular signaling pathways that control cell proliferation, survival, apoptosis, and immune function.1
  • TRAIL preferentially initiates the extrinsic apoptotic pathway2:
    • TRAIL can bind as a trimer to membrane-bound or soluble receptors, but it is only the two closely related cell surface death receptors TRAIL-R1 (DR4) and TRAIL-R2 (DR5), which express intracellular functional death domains, that can preferentially trigger the extrinsic pathway 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

Studies have demonstrated that TRAIL can selectively trigger apoptosis in tumor cells across a wide range of tumor types, including colorectal cancer, gastric cancer, pancreatic cancer, acute myeloid leukemia and non-Hodgkin lymphoma.4-7

The BCL-2 family member-driven mitochondrial intrinsic apoptotic pathway can serve to amplify the extrinsic pathway through further downstream activation of caspases.2

Acute Myeloid Leukemia (AML)

  • TRAIL serum concentrations have been shown to be significantly lower than normal in patients with newly-diagnosed AML. TRAIL concentrations were also higher in patients that responded to induction therapy compared with patients that did not respond.8
  • Low serum concentrations of TRAIL predicted a shorter overall survival.8
  1. 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.
  2. 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.
  3. 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.
  4. Johnstone RW, Frew AJ, Smyth MJ. The TRAIL apoptotic pathway in cancer onset, progression and therapy. Nature Reviews. 2008;8:782-798.
  5. 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.
  6. 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.
  7. Cassier PA, Castets M, Belhabri A, Vey N. Targeting apoptosis in acute myeloid leukaemia. Br J Cancer. 2017;117(8):1089-1098.
  8. 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.

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