Abstract
Simple SummaryAmong the plethora of malignancies affecting the female reproductive tract, those concerning the ovary are the most frequently fatal. In particular, chemotherapy-resistant High-Grade Serous Ovarian Cancer (HGSOC) remains a clinically intractable disease with a high rate of mortality. We previously identified SLC25A40-ABCB1 transcriptional fusions as the driving force behind drug resistance in HGSOC. As success in the clinical arena will only be achieved by enhancing our fundamental understanding of the drivers that mediate cellular drug resistance, this report sought to elucidate the phenotypic, metabolomic and transcriptional consequences of SLC25A40-ABCB1 fusions beyond drug resistance. High-throughput FDA drug screening was also undertaken to identify new therapeutic avenues against drug-resistant cellular populations.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.
Highlights
The invariable emergence of drug resistance following initial response to chemotherapy and limited molecularly targeted approaches continue to be the principal limiting factor to achieving cures in patients with cancer
ABCB1 fusion events were only detected in High-Grade Serous Ovarian Cancer (HGSOC) patients who had been exposed to known ABCB1 substrate chemotherapies, with the probability of a fusion event being closely correlated to the number of lines of substrate chemotherapy administered [13]
In order to decipher the biological consequences of SLC25A40-ABCB1 fusions beyond drug resistance, we utilized our AOCS18.5 HGSOC patient-derived cell line [13] which contains approximately 40% fusion-positive cells
Summary
The invariable emergence of drug resistance following initial response to chemotherapy and limited molecularly targeted approaches continue to be the principal limiting factor to achieving cures in patients with cancer. ABC transporters differ from classical selective transporters by way of their promiscuity for structurally and chemically diverse substrates (>200) and contribute to tumor biology independently of their ability to efflux cytotoxic drugs [15] This family of 48 transporters is involved in lipid export/homeostasis and mediates the release of bioactive lipids (phospholipids and sphingolipids) that activate signaling cascades involved in cellular proliferation, migration and tumorigenesis [16,17]. As the emergence of therapy resistance is generally viewed as an evolutionary process in which cancer cells adapt to selection pressures mediated by cytotoxic drugs, this study has focused on elucidating the underlying biology of drug-resistant ABCB1 fusion-positive cells and how this distinctive phenotype, in combination with evolutionary dynamics, can be clinically exploited. Using a panel of single-cell SLC25A40-ABCB1 fusion-negative and positive clones, our study sought to elucidate the complex underlying biology of fusion-positive cells beyond drug resistance as well as identify therapeutic options that can be utilized to combat this nefarious population of cells
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