The study, led by researchers at the MRC Weatherall Institute of Molecular Medicine and the Department of Oncology, identifies a cellular recycling process called nucleophagy as a key driver of treatment resistance. The findings could help improve therapies for patients with difficult-to-treat cancers, including triple-negative breast cancer.
PARP inhibitors are designed to kill cancer cells by trapping a protein called PARP1 on damaged DNA. This blocks normal DNA repair processes and causes cancer cells to die. While these drugs have transformed treatment for some patients, many cancers eventually become resistant, limiting their long-term effectiveness.
The new study found that cancer cells can survive treatment by actively removing trapped PARP1 through nucleophagy, a specialised form of autophagy that clears material from the cell nucleus.
The researchers identified a protein called TEX264 as a critical mediator of this process. TEX264 recognises trapped PARP1 and directs it towards the cell’s degradation machinery, allowing cancer cells to clear the toxic damage and continue growing despite treatment.
When the researchers disrupted TEX264-driven nucleophagy, trapped PARP1 accumulated inside cancer cells, leading to increased DNA damage and significantly higher levels of cancer cell death. Importantly, blocking this pathway also restored sensitivity to PARP inhibitors in cancer cells that had previously become resistant.
"Our findings reveal a completely new mechanism by which cancer cells can evade PARP inhibitor therapy," said Professor Kristijan Ramadan, senior author of the study. "By targeting TEX264-driven nucleophagy, we may be able to overcome resistance and improve outcomes for patients whose cancers no longer respond to these treatments."
The study also revealed potential clinical significance for TEX264 as a biomarker. Analysis of patient data showed that individuals with triple-negative breast cancer who had low TEX264 expression experienced approximately 30% better overall survival over ten years compared with patients whose tumours expressed high levels of TEX264.
These findings suggest that TEX264 could help predict patient outcomes and guide more personalised treatment approaches in the future.
The research involved collaborators from the University of Bern, the Institute of Cancer Research in London, Penn State College of Medicine, the University of Coimbra, Nanyang Technological University Singapore, and other international partners.
The paper, "Nucleophagy removes cytotoxic trapped PARP1", published in Nature Cell Biology, identifies TEX264-driven nucleophagy as both a promising therapeutic target and a potential biomarker for improving cancer treatment outcomes. The discovery opens new avenues for tackling drug resistance and enhancing the effectiveness of precision cancer therapies.
Read the article here.