Biology subjects

McNally, O.

Publications and source records attributed to McNally, O..

2 recordsLinked to original sources

bioRxiv2020

Acquired RAD51C promoter methylation loss causes PARP inhibitor resistance in high grade serous ovarian carcinoma

While loss of BRCA1 promoter methylation has been shown to cause PARP inhibitor (PARPi) resistance in high-grade serous ovarian carcinoma (HGSC), the impacts of RAD51C methylation (meRAD51C) remain unresolved. In this study, three PARPi-responsive HGSC patient-derived xenografts (PDX) with RAD51C gene silencing and homologous recombination deficiency were found to have either homogeneous or heterogeneous patterns of meRAD51C. PDX could lose meRAD51C following PARPi treatment (rucaparib/niraparib), where a single unmethylated RAD51C copy was sufficient to drive PARPi-resistance. Genomic profiling revealed this resistance was acquired independently in two distinct PDX lineages. Furthermore, we describe a patient sample where 1/3 RAD51C gene copies lost methylation following neoadjuvant chemotherapy. We show meRAD51C is a positive predictive biomarker for PARPi response and should be screened for routinely in patients. However, methylation loss in a single gene copy is sufficient to cause PARPi resistance and should be carefully assessed in previously treated patients considering PARPi therapy.

cancer biology↗

bioRxiv2020

Ovarian carcinosarcoma genomics and pre-clinical models highlight the N-MYC pathway as a key driver and susceptibility to EMT-targeting therapy

Ovarian carcinosarcoma (OCS) is an aggressive and rare tumour type with limited treatment options. OCS is hypothesised to develop via the combination theory from a single progenitor, resulting in carcinomatous and sarcomatous components, or alternatively via the conversion theory, with the sarcomatous component developing from the carcinomatous component through epithelial-to-mesenchymal transition (EMT). We show OCS from 18 women to be monoclonal through analysis of DNA variants from isolated carcinoma and sarcoma components. RNA sequencing indicated the carcinoma components were more mesenchymal when compared with pure ovarian carcinomas, supporting the conversion theory. We used pre-clinical OCS models to test the efficacy of microtubule-targeting drugs, including eribulin, which has been shown to reverse EMT characteristics. We demonstrated that microtubule inhibitors, vinorelbine and eribulin, were more effective than standard-of-care platinum-based chemotherapy. Eribulin reduced mesenchymal characteristics, N-MYC expression and cholesterol biosynthesis. Finally, eribulin induced a strong immune response, supporting immunotherapy combinations in the clinic.

cancer biology↗