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Nucleophagy as an emerging therapeutic vulnerability in cancer

Sara Tribble1, Kristijan Ramadan1,2

  • 1MRC Weatherall Institute of Molecular Medicine, Department of Oncology, John Radcliffe Hospital, University of Oxford, Oxford, UK.

Autophagy
|July 24, 2026
PubMed

Insights

Poly(ADP-ribose) polymerase inhibitors (PARPi) trap PARP1 in cancer cells, but resistance is common. A new pathway involving TEX264-mediated nucleophagy clears trapped PARP1, offering a potential strategy against PARPi resistance in homologous recombination-deficient cancers.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Genetics

Background:

  • Poly(ADP-ribose) polymerase inhibitors (PARPi) are effective against homologous recombination-deficient (HRD) cancers by inducing synthetic lethality.
  • Resistance to PARPi is a significant clinical hurdle, limiting their long-term efficacy.
  • The precise mechanisms resolving cytotoxic PARP1 trapping remain incompletely understood.

Purpose of the Study:

  • To elucidate a novel mechanism for the clearance of DNA-trapped PARP1.
  • To identify new therapeutic targets for overcoming PARPi resistance in HRD cancers.

Main Methods:

  • Investigated the role of TEX264 in resolving PARP1 trapping using cell-based assays.
  • Utilized molecular biology techniques to analyze the p97-TEX264-nucleophagy pathway.
  • Assessed the impact of targeting this pathway on PARPi sensitivity in HRD cancer models.

Main Results:

  • Discovered that TEX264 mediates nucleophagy, a pathway for clearing cytotoxic trapped PARP1.
  • Identified the p97-TEX264-nucleophagy axis as crucial for removing PARP1-DNA complexes.
  • Demonstrated that this pathway is a key determinant of sensitivity and resistance to PARPi.

Conclusions:

  • The p97-TEX264-nucleophagy axis represents a previously unrecognized mechanism for resolving PARPi-induced DNA damage.
  • Targeting this pathway holds promise for overcoming primary and acquired resistance to PARPi in HRD cancers.
  • This finding opens new avenues for combination therapies to enhance PARPi efficacy.
Keywords:
Homologous recombination deficiencyPARP1 trappingTEX264nucleophagysynthetic lethalitytherapeutic resistance

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