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Trip12 as determinant of parp inhibitor therapy

Principal Investigators

Matthias Altmeyer, Department of Molecular Mechanisms of Disease, University of Zurich
Konstantin Dedes, Gynecological Cancer Center, Department of Gynecology, University Hospital Zurich

Fellow

Aswini Krishnan, PhD

Keywords

PARP inhibitors, BRCA deficiency, olaparib, PARP trapping, breast & ovarian cancer, personalized cancer therapy

Summary

PARP inhibitors (PARPi) are the first-in-class targeted cancer therapeutics that have entered the clinics based on the concept of synthetic lethality. PARPi-induced synthetic lethality is achieved in the context of defects in genome integrity maintenance by homology-directed repair (HDR), in particular in breast and ovarian cancer patients with BRCA mutations. As PARPi are well tolerated and can be used either as single agents or in combination therapy, there is a need to identify biomarkers that can predict PARPi responses, and to explore whether PARPi can be applied for cancer therapy beyond patients with BRCA mutations or HDR defects. We recently established a quantitative multidimensional high-content-microscopy-based pipeline to assess PARPi responses and predict PARPi sensitivity and resistance (Michelena et al., Nature Communications, 2018). Using this experimental pipeline, we performed targeted screens to uncover cellular determinants of PARPi sensitivity and identified the HECT-type ubiquitin ligase TRIP12 as negative regulator of PARP1, which constrains PARPi efficiency (Gatti et al., Cell Reports, 2020). We could show that TRIP12 determines PARP1 stability and PARPi induced PARP1 trapping on chromatin, and that reduced TRIP12 expression causes increased PARP1 trapping and consequently elevated PARPi-induced DNA replication stress, DNA damage, cell cycle arrest, and cell death. Of note, these effects were independent of BRCA status, suggesting that TRIP12 determines PARPi efficiency in both BRCA-proficient and BRCA-deficient cancer cells. Further, by multi-omics analyses of available datasets from human breast and ovarian cancer patients we found a significant negative correlation between TRIP12 expression and PARP1 abundance, again irrespective of BRCA status. Taken together, these results suggest that TRIP12 status influences PARP1 stability, PARPi-induced PARP1 trapping, and hence PARPi response. In this collaborative project, involving basic scientists from UZH and clinical scientists from USZ Gynecology and Pathology, we aim to establish TRIP12 status as a clinical marker for PARPi response, with the prospect that TRIP12 measurements could rationalize the use of PARPi beyond BRCA mutations and HDR defects, and thereby help expand and stratify the group of cancer patients that may benefit from PARPi therapy.