PADI-dependent mitochondrial adaptation drives resistance to KRAS inhibitors.

PADI1 and PADI3 promote resistance to KRAS inhibitors by sustaining mitochondrial adaptation in KRAS-driven tumors.

• Why it matters: Overcoming resistance to KRAS-targeted therapies is crucial for improving treatment outcomes in KRAS-mutant cancers, yet the mechanisms behind this resistance are not fully understood.
• What they did: The study examined PADI1/3 expression in KRAS-mutant colorectal and pancreatic cancers, using pharmacological inhibitors and multi-omics analyses to explore their role in resistance and mitochondrial function.
• The result: Inhibiting PADIs restores sensitivity to KRAS inhibitors, induces mitochondrial dysfunction, and triggers apoptosis, revealing a new therapeutic vulnerability to target resistant KRAS-driven tumors.