ONC201 kills solid tumor cells by triggering an integrated stress response dependent on ATF4 activation by specific...

Area of Science:

• Molecular Biology
• Cancer Research
• Cell Death Signaling

Background:

• ONC201 (TIC10) is an investigational small molecule targeting cancer cell proliferation and survival.
• It functions by inhibiting Akt and ERK kinases and inducing apoptosis via TRAIL.
• ONC201 is undergoing early-phase clinical trials for various cancers.

Purpose of the Study:

• To elucidate the molecular mechanisms by which ONC201 induces cancer cell death.
• To investigate the role of the integrated stress response (ISR) pathway in ONC201's action.
• To determine if ONC201's efficacy is dependent on p53 status.

Main Methods:

• Gene expression and protein analyses were employed.
• Knockdown studies were performed for ATF4 and CHOP.
• Cell cycle analysis and assessment of protein abundance (e.g., cyclin D1, XIAP) were conducted.

Main Results:

• ONC201 treatment increased TRAIL and DR5, mediated by the ISR pathway components ATF4 and CHOP.
• ATF4 activation, dependent on HRI and PKR kinases, was crucial for ONC201-induced cytotoxicity and DR5 upregulation.
• ONC201 induced cell cycle arrest, decreased mTORC1 activity, and dephosphorylated Rb, with XIAP inversely correlating with apoptosis.
• These effects were observed in cancer cells with both normal and mutant p53.

Conclusions:

• ONC201 induces cancer cell death through a p53-independent integrated stress response (ISR) pathway.
• The ISR pathway culminates in the coordinated induction of TRAIL and DR5, promoting apoptosis.
• ONC201's mechanism involves cell cycle arrest and modulation of key cell survival/death proteins.