Journal
FEBS OPEN BIO
Volume 11, Issue 3, Pages 714-723Publisher
WILEY
DOI: 10.1002/2211-5463.13096
Keywords
apoptosis; ASTX660; SMAC mimetic; TNF; TRAIL
Categories
Funding
- Universitatsstiftung Helga und Erwin Hartl [008/2020]
- Universitatsstiftung Angela Schotz-Keilholz [001/2020]
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Resistance to apoptosis in cancer worsens treatment response and prognosis. Targeting anti-apoptotic proteins like cIAP1, cIAP2, and XIAP with compounds like ASTX660 can restore cell death and improve treatment efficacy. ASTX660, a non-peptidomimetic IAP antagonist, has shown promising results in promoting cell death in colorectal cancer.
Apoptosis resistance worsens treatment response in cancer and is associated with poor prognosis. Inhibition of anti-apoptotic proteins can restore cell death and improve treatment efficacy. cIAP1, cIAP2, and XIAP belong to the inhibitor of apoptosis protein (IAP) family and block apoptosis. Targeting IAPs with peptides or peptidomimetics mimicking the IAP-antagonizing activity of the cell's endogenous IAP antagonist SMAC (SMAC mimetics) showed promising results and fueled development of novel compounds. ASTX660 belongs to the recently introduced class of non-peptidomimetic IAP antagonists and successfully completed phase I clinical trials. However, ASTX660 has thus far only been evaluated in few cancer entities. Here, we demonstrate that ASTX660 has cell death-promoting activity in colorectal cancer and provide a head-to-head comparison with birinapant, the clinically most advanced peptidomimetic IAP antagonist. ASTX660 facilitates activation of the extrinsic apoptosis pathway upon stimulation with the death ligands TNF and TRAIL and boosts effector caspase activation and subsequent apoptosis. Mechanistically, ASTX660 enhances amplification of death receptor-generated apoptotic signals in a mitochondria-dependent manner. Failure to activate the mitochondria-associated (intrinsic) apoptosis pathway attenuated the apoptosis-promoting effect of ASTX660. Further clinical studies are warranted to highlight the therapeutic potential of ASTX660 in colorectal cancer.
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