Selective Autophagy of Trapped PARP1 as a Therapeutic Target in Breast Cancer

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Summary of  Nature Cell Biology https://doi.org/10.1038/s41556-026-01961-5 
Dr. Gwendoline Hoslett  et al.

Points

Nanyang Technological University researchers identified TEX264-mediated nucleophagy as a novel biological mechanism driving PARP inhibitor resistance in cancer cells.
Experimental results showed that PARP inhibitor exposure increased TEX264 binding to trapped PARP1 by 40% to direct autophagosomal degradation.
Blocking TEX264 function increased chromatin-bound PARP1 by 70% and elevated DNA damage metrics by 40% to 110% in resistant tumors.
Clinical data from 700 triple-negative breast cancer patients revealed that low TEX264 levels correlated with a 28% higher 10-year survival rate.
Combining PARP inhibitors with clinically approved autophagy inhibitors like hydroxychloroquine offers a novel strategy to overcome treatment resistance in aggressive HRD cancers.

Summary

This study evaluated the molecular mechanisms driving PARP inhibitor (PARPi) resistance in homologous recombination repair-deficient (HRD) cancers, focusing on the role of selective nucleophagy in clearing chromatin-trapped PARP1. PARP inhibitors exert cytotoxicity by trapping PARP1 on damaged DNA, generating lethal replication-associated lesions. However, cancer cells frequently acquire resistance by enhancing trapped PARP1 removal. Researchers sought to determine whether the selective autophagy receptor TEX264 and its partner segregase p97/VCP orchestrate the degradation of trapped PARP1 to promote tumor cell survival.

In vitro experiments demonstrated that PARPi exposure induced a 40% increase in TEX264 binding to trapped PARP1, linking it directly to autophagosomal LC3 for nuclear clearance. Blocking autophagy produced a 70% increase in persistent chromatin-bound PARP1. Genetic or pharmacological disruption of TEX264-mediated nucleophagy increased total DNA damage metrics by 40% to 110% across indicators, restoring drug sensitivity and inducing apoptosis in resistant cells. Clinical correlation using data from 700 triple-negative breast cancer (TNBC) patients in the SCAN-B cohort revealed that low TEX264 expression was associated with a 28% higher 10-year overall survival rate compared to high expression levels.

These findings establish TEX264-driven nucleophagy as a major cytoprotective mechanism that clears drug-induced PARP1-DNA complexes to cause PARPi resistance. Co-targeting TEX264 or downstream autophagic pathways using clinically approved agents—such as chloroquine or hydroxychloroquine—presents a promising combination strategy to overcome therapeutic resistance. Furthermore, TEX264 expression serves as a predictive prognostic biomarker for personalized treatment stratification in aggressive, HRD-positive malignancies.

Link to the article: https://www.nature.com/articles/s41556-026-01961-5

References

Hoslett, G., Tribble, S., Lascaux, P., Koukouravas, S., Torrecilla, I., Song, W., Hou, C. X., Li, J., González-Fernández, M., De Gregoriis, G., Dagg, R. A., O’Brien, D., Pierangelini, A., Martial, T., Ng, A. W. T., Raimundo, N., Milosevic, I., Freire, R., Li, Y., … Ramadan, K. (2026). Nucleophagy removes cytotoxic trapped PARP1. Nature Cell Biology, 28(6), 1219–1234. https://doi.org/10.1038/s41556-026-01961-5