KRAS-mutated cancers evade ferroptosis via CCDC6 degradation, upregulating xCT and glutathione

Oncogenic KRAS mutations are a major driver of tumorigenesis, promoting cell survival and metabolic reprogramming. A critical aspect of this involves maintaining redox balance to counteract oxidative stress, a key defense against cell death pathways like ferroptosis. The xCT cystine/glutamate antiporter is crucial for this, sustaining glutathione (GSH) synthesis. While the ETS1-ATF4 complex is known to transcriptionally upregulate xCT, the precise upstream regulators linking KRAS signaling to this axis, and thus to ferroptosis evasion, have remained incompletely defined.

Researchers investigated the link between oncogenic KRAS and ferroptosis resistance using KRAS-mutated cancer cell lines, preclinical models, and human colorectal cancer samples. They examined the role of CCDC6 by inducing its degradation and then inhibiting its turnover using proteasome, GSK3β, or specific KRAS mutant inhibitors such as Sotorasib, Adagrasib, and HRS4642. Cells were then challenged with ferroptosis-inducing agents like Sulfasalazine to assess sensitization. Protein levels were analyzed, and ATF4 recruitment to the xCT promoter was investigated.

Oncogenic KRAS signaling was found to induce the GSK3β-mediated proteasomal degradation of the tumor suppressor CCDC6. This degradation is crucial because CCDC6 acts as a negative regulator of the xCT-promoting transcription factor ATF4 by directly interacting with it and preventing its recruitment to the xCT promoter. Consequently, KRAS-driven CCDC6 degradation disinhibits ATF4, leading to increased xCT expression, elevated intracellular GSH, and enhanced resistance to ferroptosis. This establishes a novel KRAS/CCDC6/xCT signaling axis. > Crucially, pharmacological inhibition of CCDC6 turnover using proteasome, GSK3β, or specific KRAS mutant inhibitors (Sotorasib, Adagrasib, HRS4642) restored CCDC6 protein levels and robustly sensitized KRAS-mutated cells to ferroptosis-inducing agents like Sulfasalazine. Furthermore, validation in preclinical models and human colorectal cancer samples revealed that CCDC6 protein levels are predominantly downregulated in KRAS-mutant cases.