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P97-UFD1-LARP1 axis regulates autophagy and PARP inhibitor resistance in ovarian cancer


   Department of Oncology

  ,  Friday, December 09, 2022  Competition Funded PhD Project (Students Worldwide)

About the Project

Ovarian cancer (OC) is the most lethal gynaecological malignancy. The majority of the 240,000 women annually diagnosed with OC die within 5 years.1 These grim survival figures have barely improved over the last 30 years despite the introduction of DNA-damaging platinum chemotherapy (like carboplatin or cisplatin) and PARP inhibitors (PARPi), both mainstays of treatment. The reason for its high mortality is that OC rapidly acquires resistance to these drugs and patients die from complications of progressive treatment-resistant cancer.2 A key to this resistance is in the repair of damaged DNA. In OC, single-stranded DNA damage is repaired by PARP1 protein. PARP inhibitors like talazopanib work by ‘trapping’ PARP1 protein onto damaged DNA which causes further damage and cell death. However, OC cells become resistant to PARPi by removing and destroying both the trapped PARP1 and the damaged DNA. We have recently identified that this is achieved by specialised DNA repair machinery,3 composed of the ATPase p97, the ubiquitin receptor and p97-cofactor UFD1, and the mRNA-binding and p97-interacting protein LARP1. This p97-UFD1-PARP1 complex attaches to trapped PARP1 and removes it in an autophagy-dependent manner. Autophagy is a waste-disposal process whereby redundant cellular materials are collected into vesicles called autophagosomes and digested using enzymes.4 Although autophagy has long been associated with chemotherapy-resistance, the reason for this link has remained unknown. Autophagy inhibitors like hydroxychloroquine (clinically approved for malaria) have been used in anticancer clinical trials but, in some case, worsen chemotherapy resistance rather than reverse it.5 Our discovery of the p97-UFD1-LARP1 complex is an important step into resolving this conundrum. Here, we wish to understand how the p97-UFD1-LARP1 complex uses autophagy to remove trapped PARP1 from DNA and contributes to PARP inhibitor resistance. Our findings have the potential to address the unmet medical need over overcoming PARP resistance, a prognostically ominous event.


References

Krastev, D.B., Li, S., Sun, Y., Wicks, A.J., Hoslett, G., Weekes, D., Badder, L.M., Knight, E.G., Marlow, R., Pardo, M.C. and Yu, L., 2022. The ubiquitin-dependent ATPase p97 removes cytotoxic trapped PARP1 from chromatin. Nature cell biology, 24(1), pp.62-73.
Chettle, J., Dedeic, Z., Fischer, R., Vendrell, I., Campo, L., Easton, A., Browne, M., Morris, J., Schwenzer, H., Lascaux, P. and Gijsbers, R., 2022. LARP1 regulates metabolism and mTORC1 activity in cancer. bioRxiv. doi; https://doi.org/10.1101/2022.09.04.506559

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