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Peer-reviewedCC BY-NC-ND 4.0Cell Reports

PADI-dependent mitochondrial adaptation drives resistance to KRAS inhibitors

  • Mariachiara Gani1
  • Francesca Agostini1
  • Luca Secco2
  • Lavinia De Pino1
  • Raffaella Picco1
  • Danilo Licastro3
  • Vanessa Tolotto1
  • Francesca D’Este1
  • Himanshi Choudhary1
  • Annalisa Ferino1
  • Valentina Rapozzi1
  • Leonard Barasa4
6 more authors
  • Yuhei Ohta5
  • Hidehiko Nakagawa5
  • Riccardo Sgarra2
  • Paul R. Thompson4
  • Luigi E. Xodo1
  • Eros Di Giorgio1
5 affiliations
  1. 1Laboratory of Biochemistry, Department of Medicine, University of Udine, Piazzale M. Kolbe 4, 33100 Udine, Italy
  2. 2Life Sciences Department, University of Trieste, 34127 Trieste, Italy
  3. 3AREA Science Park, 34149 Trieste, Italy
  4. 4Department of Biochemistry and Molecular Biotechnology, University of Massachusetts Chan Medical School, 364 Plantation Street, Worcester, MA 01605, USA
  5. 5Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, 467-8603 Nagoya, Japan
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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.

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Cite

BibTeXRIS
BibTeX
@article{gani2026padidependent,
  title = {{PADI-dependent mitochondrial adaptation drives resistance to KRAS inhibitors}},
  author = {Mariachiara Gani and Francesca Agostini and Luca Secco and Lavinia De Pino and Raffaella Picco and Danilo Licastro and Vanessa Tolotto and Francesca D’Este and Himanshi Choudhary and Annalisa Ferino and Valentina Rapozzi and Leonard Barasa and Yuhei Ohta and Hidehiko Nakagawa and Riccardo Sgarra and Paul R. Thompson and Luigi E. Xodo and Eros Di Giorgio},
  journal = {Cell Reports},
  year = {2026},
  month = sep,
  doi = {10.1016/j.celrep.2026.118016},
  url = {https://doi.org/10.1016/j.celrep.2026.118016},
  note = {CC BY-NC-ND 4.0},
}
RIS
TY  - JOUR
TI  - PADI-dependent mitochondrial adaptation drives resistance to KRAS inhibitors
AU  - Mariachiara Gani
AU  - Francesca Agostini
AU  - Luca Secco
AU  - Lavinia De Pino
AU  - Raffaella Picco
AU  - Danilo Licastro
AU  - Vanessa Tolotto
AU  - Francesca D’Este
AU  - Himanshi Choudhary
AU  - Annalisa Ferino
AU  - Valentina Rapozzi
AU  - Leonard Barasa
AU  - Yuhei Ohta
AU  - Hidehiko Nakagawa
AU  - Riccardo Sgarra
AU  - Paul R. Thompson
AU  - Luigi E. Xodo
AU  - Eros Di Giorgio
PY  - 2026
DA  - 2026/09/17
JO  - Cell Reports
DO  - 10.1016/j.celrep.2026.118016
UR  - https://doi.org/10.1016/j.celrep.2026.118016
AB  - 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.
SN  - 2211-1247
ER  -