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Author Spotlight: Quantitative Detection of DNA Protein Crosslinks and Their Post-Translational Modifications
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A PP2A-mtATR-tBid axis links DNA damage-induced CIP2A degradation to apoptotic dormancy and therapeutic resistance in

Yibo Luo1, Himadri Biswas1, Yetunde Makinwa1

  • 1Department of Cell and Cancer Biology, University of Toledo College of Medicine and Life Sciences, Toledo, OH, 43614, USA.

Cancer Letters
|May 12, 2025
PubMed

Insights

Researchers discovered a new way cancer cells resist chemotherapy. In pancreatic cancer, a protein complex (mtATR-tBid) stops cell death. Inhibiting this complex restores chemotherapy effectiveness against resistant tumors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Chemotherapy resistance is a major obstacle in cancer treatment, particularly for DNA damage-based drugs like gemcitabine.
  • Pancreatic ductal adenocarcinoma (PDAC) frequently develops resistance, necessitating novel therapeutic strategies.
  • Understanding non-DNA repair mechanisms of resistance is crucial for overcoming treatment failure.

Purpose of the Study:

  • To elucidate a novel non-DNA repair mechanism driving gemcitabine resistance in PDAC.
  • To identify therapeutic targets that can restore sensitivity to DNA damage-based chemotherapy.
  • To investigate the role of the CIP2A-PP2A-ATR axis in chemoresistance.

Main Methods:

  • Utilized gemcitabine-resistant PDAC cell lines and an orthotopic PDAC mouse model.
  • Investigated protein degradation pathways, phosphatase activity, and protein complex formation.
  • Employed PP2A inhibitor (LB-100) and specific antibodies to disrupt the identified complex.

Main Results:

  • Gemcitabine-resistant PDAC cells exhibit CIP2A degradation, leading to increased PP2A activity and cytoplasmic ATR dephosphorylation.
  • Dephosphorylated ATR forms a mitochondria-targeted antiapoptotic protein (mtATR), which complexes with tBid, inducing apoptotic dormancy.
  • Disruption of the mtATR-tBid complex by LB-100 or an ATR antibody restores apoptosis and inhibits tumor growth in vivo.

Conclusions:

  • A novel mechanism of chemoresistance involving CIP2A degradation, PP2A activation, and the formation of a pro-apoptotic complex (mtATR-tBid) was identified in PDAC.
  • Targeting the mtATR-tBid complex represents a promising strategy to overcome gemcitabine resistance.
  • LB-100 demonstrates efficacy by disrupting this complex, offering a potential therapeutic approach for resistant pancreatic cancer.
Keywords:
And LB-100Apoptotic dormancyCIP2ADNA damageMitochondrial ATR-tBid complexPDAC drug resistance

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