Abstract 2984: Heterogeneous mechanisms of acquired resistance in high grade serous ovarian cancer

Several poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors are now in clinical use for tumours with defects in BReast CAncer genes BRCA1 or BRCA2 that result in deficient homologous recombination repair (HRR). Use of olaparib, niraparib or rucaparib for the treatment of high-grade serous ovarian cancer, including in the maintenance setting, has extended both progression free and overall survival for women with this malignancy. While different PARP inhibitors (PARPis) are mechanistically similar, differences are apparent in their chemical structures, toxicity profiles, PARP trapping abilities and polypharmacological landscapes. We have treated ovarian cancer cell line models of known BRCA status, including the paired cell lines PEO1 and PEO4, and UWB1.289 and UWB1.289+BRCA1, with five PARPis (olaparib, niraparib, rucaparib, talazoparib and veliparib) and observed differences between PARPis in both cell viability and cell survival. A cell line model of acquired resistance to veliparib showed increased resistance to the other four PARPis tested, suggesting that acquired resistance to one PARPi may not be able to be rescued by another. Lastly, as a proof of principle, HRR proficient ovarian cancer cells were sensitised to PARPis by depletion of BRCA1. In the future, guidelines will need to emerge to assist clinicians in matching specific PARPis to specific patients and tumours.

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AKT Isoforms Interplay in High-Grade Serous Ovarian Cancer Prognosis and Characterization

Cancers ◽

10.3390/cancers14020304 ◽

2022 ◽

Vol 14 (2) ◽

pp. 304

Author(s):

Eros Azzalini ◽

Domenico Tierno ◽

Michele Bartoletti ◽

Renzo Barbazza ◽

Giorgio Giorda ◽

...

Keyword(s):

Ovarian Cancer ◽

Acquired Resistance ◽

Digital Pcr ◽

Parp Inhibitors ◽

Clinicopathological Features ◽

Cancer Prognosis ◽

High Grade ◽

Serous Ovarian Cancer ◽

Akt Isoforms ◽

Ovarian Cancer Prognosis

High-grade serous ovarian cancer (HGSOC) is among the deadliest gynecological malignancies. The acquired resistance to platinum-based therapies and the intrinsic heterogeneity of the disease contribute to the low survival rate. To improve patients’ outcomes, new combinatorial approaches able to target different tumor vulnerabilities and enhance the efficacy of the current therapies are required. AKT inhibitors are promising antineoplastic agents able to act in synergy with PARP inhibitors, but the spectrum of patients who can benefit from this combination is unclear, since the role of the three different isoforms of AKT is still unknown. Here, we study the expression of AKT isoforms on a retrospective cohort of archive tissue by RT-droplet digital PCR (ddPCR) analyzing their association with the clinicopathological features of patients. Based on AKT1/AKT2 and AKT1/AKT3 ratios, we define four AKT classes which were related to patients’ survival, tumor morphology and BRCA1 expression. Moreover, our results show that high AKT3 expression levels were frequently associated with tumors having classic features, a low number of mitoses and the presence of psammoma bodies. Overall, our study obtains new insights on AKT isoforms and their associations with the clinicopathological features of HGSOC patients. These evidences could help to better define the subsets of patients who can benefit from AKT and PARP inhibitors therapy in future clinical trials.

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Phenotypic Consequences of SLC25A40-ABCB1 Fusions beyond Drug Resistance in High-Grade Serous Ovarian Cancer

Cancers ◽

10.3390/cancers13225644 ◽

2021 ◽

Vol 13 (22) ◽

pp. 5644

Author(s):

Kathleen I. Pishas ◽

Karla J. Cowley ◽

Ahwan Pandey ◽

Therese Hoang ◽

Jessica A. Beach ◽

...

Keyword(s):

Ovarian Cancer ◽

Drug Resistance ◽

High Throughput Screening ◽

Cellular Proliferation ◽

Acquired Resistance ◽

Common Mechanism ◽

High Grade ◽

Serous Ovarian Cancer ◽

Cell Clones ◽

Transcriptional Fusions

Despite high response rates to initial chemotherapy, the majority of women diagnosed with High-Grade Serous Ovarian Cancer (HGSOC) ultimately develop drug resistance within 1–2 years of treatment. We previously identified the most common mechanism of acquired resistance in HGSOC to date, transcriptional fusions involving the ATP-binding cassette (ABC) transporter ABCB1, which has well established roles in multidrug resistance. However, the underlying biology of fusion-positive cells, as well as how clonal interactions between fusion-negative and positive populations influences proliferative fitness and therapeutic response remains unknown. Using a panel of fusion-negative and positive HGSOC single-cell clones, we demonstrate that in addition to mediating drug resistance, ABCB1 fusion-positive cells display impaired proliferative capacity, elevated oxidative metabolism, altered actin cellular morphology and an extracellular matrix/inflammatory enriched transcriptional profile. The co-culture of fusion-negative and positive populations had no effect on cellular proliferation but markedly altered drug sensitivity to doxorubicin, paclitaxel and cisplatin. Finally, high-throughput screening of 2907 FDA-approved compounds revealed 36 agents that induce equal cytotoxicity in both pure and mixed ABCB1 fusion populations. Collectively, our findings have unraveled the underlying biology of ABCB1 fusion-positive cells beyond drug resistance and identified novel therapeutic agents that may significantly improve the prognosis of relapsed HGSOC patients.

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