Synthetic lethal screening identifies compounds activating iron-dependent, nonapoptotic cell death in...

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Oncogenic RAS mutations drive cancer growth.
• Targeting RAS-driven cancers remains a significant challenge.
• RAS-selective compounds induce oxidative cell death.

Purpose of the Study:

• Identify novel compounds targeting oncogenic RAS.
• Elucidate the mechanism of action for these compounds.
• Investigate the role of iron in RAS-driven cell death.

Main Methods:

• Small molecule screening to identify RSL3 and RSL5.
• Counter screening and mechanistic studies.
• RNA interference targeting voltage-dependent anion channels (VDACs).

Main Results:

• RSL3 and RSL5 exhibit increased lethality in oncogenic RAS cells.
• Cell death is non-apoptotic, MEK-dependent, and iron-dependent.
• RSL5 acts via VDACs, while RSL3 acts independently.
• RAS-transformed cells show increased iron content.

Conclusions:

• RSL3 and RSL5 are potent inducers of oxidative cell death in RAS-driven cancers.
• The mechanism involves iron dysregulation and MEK signaling.
• These compounds represent potential therapeutic agents for RAS-mutated tumors.