KRAS(ON) and KRAS(OFF) inhibitors have improved the treatment of KRAS-driven tumors, yet resistance remains a major challenge. Here, we identify PADI1 and PADI3 as negative prognostic markers in KRAS-mutant colorectal and pancreatic cancers. KRAS-driven metabolic rewiring sustains their expression through an enhancer within the PADI1 locus. Although KRAS inhibition suppresses PADI1/3 expression in sensitive cells, resistant models maintain elevated PADI1/3 expression and accumulate intracellular calcium, sustaining PADI-dependent adaptive survival. Pharmacological inhibition of PADIs synergizes with KRAS(ON) and KRAS(OFF) inhibitors in two- and three-dimensional cancer models, restores sensitivity in resistant cells, and enhances antitumor activity in vivo. Integrated transcriptomic and proteomic analyses identify HSPA9/Mortalin as a critical citrullinated effector. PADI3-mediated citrullination enhances Mortalin ATPase activity and ATP/ADP cycling, whereas loss of citrullination correlates with apoptosis. Disruption of this adaptive circuitry triggers mitochondrial dysfunction, caspase activation, and non-lytic apoptosis without detectable DAMP release, revealing a therapeutic vulnerability of KRAS-driven tumors.
PADI-dependent mitochondrial adaptation drives resistance to KRAS inhibitors / Gani, M., Agostini, F., Secco, L., De Pino, L., Picco, R., Licastro, D., Tolotto, V., D'Este, F., Choudhary, H., Ferino, A., Rapozzi, V., Barasa, L., Ohta, Y., Nakagawa, H., Sgarra, R., Thompson, P.R., Xodo, L.E., Di Giorgio, E.. - In: CELL REPORTS. - ISSN 2211-1247. - ELETTRONICO. - 45:10(2026), pp. 118016.--118016.-. [10.1016/j.celrep.2026.118016]
PADI-dependent mitochondrial adaptation drives resistance to KRAS inhibitors
Secco L.;De Pino L.;Licastro D.;Sgarra R.;
2026-01-01
Abstract
KRAS(ON) and KRAS(OFF) inhibitors have improved the treatment of KRAS-driven tumors, yet resistance remains a major challenge. Here, we identify PADI1 and PADI3 as negative prognostic markers in KRAS-mutant colorectal and pancreatic cancers. KRAS-driven metabolic rewiring sustains their expression through an enhancer within the PADI1 locus. Although KRAS inhibition suppresses PADI1/3 expression in sensitive cells, resistant models maintain elevated PADI1/3 expression and accumulate intracellular calcium, sustaining PADI-dependent adaptive survival. Pharmacological inhibition of PADIs synergizes with KRAS(ON) and KRAS(OFF) inhibitors in two- and three-dimensional cancer models, restores sensitivity in resistant cells, and enhances antitumor activity in vivo. Integrated transcriptomic and proteomic analyses identify HSPA9/Mortalin as a critical citrullinated effector. PADI3-mediated citrullination enhances Mortalin ATPase activity and ATP/ADP cycling, whereas loss of citrullination correlates with apoptosis. Disruption of this adaptive circuitry triggers mitochondrial dysfunction, caspase activation, and non-lytic apoptosis without detectable DAMP release, revealing a therapeutic vulnerability of KRAS-driven tumors.Pubblicazioni consigliate
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