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

1
Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia
2
The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC 3010, Australia
3
Victorian Centre for Functional Genomics, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia
4
Department of Clinical Pathology, Faculty of Medicine, Dentistry, and Health Science, The University of Melbourne, Melbourne, VIC 3000, Australia
5
Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, CA 91010, USA
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Academic Editor: Charles Theillet
Cancers 2021, 13(22), 5644; https://doi.org/10.3390/cancers13225644
Received: 28 September 2021 / Revised: 5 November 2021 / Accepted: 5 November 2021 / Published: 11 November 2021
(This article belongs to the Section Molecular Cancer Biology)
Among 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. View Full-Text
Keywords: ABCB1; high-grade serous ovarian cancer; drug resistance; high-throughput drug screening ABCB1; high-grade serous ovarian cancer; drug resistance; high-throughput drug screening
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MDPI and ACS Style

Pishas, K.I.; Cowley, K.J.; Pandey, A.; Hoang, T.; Beach, J.A.; Luu, J.; Vary, R.; Smith, L.K.; Shembrey, C.E.; Rashoo, N.; White, M.O.; Simpson, K.J.; Bild, A.; Griffiths, J.I.; Cheasley, D.; Campbell, I.; Bowtell, D.D.L.; Christie, E.L. Phenotypic Consequences of SLC25A40-ABCB1 Fusions beyond Drug Resistance in High-Grade Serous Ovarian Cancer. Cancers 2021, 13, 5644. https://doi.org/10.3390/cancers13225644

AMA Style

Pishas KI, Cowley KJ, Pandey A, Hoang T, Beach JA, Luu J, Vary R, Smith LK, Shembrey CE, Rashoo N, White MO, Simpson KJ, Bild A, Griffiths JI, Cheasley D, Campbell I, Bowtell DDL, Christie EL. Phenotypic Consequences of SLC25A40-ABCB1 Fusions beyond Drug Resistance in High-Grade Serous Ovarian Cancer. Cancers. 2021; 13(22):5644. https://doi.org/10.3390/cancers13225644

Chicago/Turabian Style

Pishas, Kathleen I., Karla J. Cowley, Ahwan Pandey, Therese Hoang, Jessica A. Beach, Jennii Luu, Robert Vary, Lorey K. Smith, Carolyn E. Shembrey, Nineveh Rashoo, Madelynne O. White, Kaylene J. Simpson, Andrea Bild, Jason I. Griffiths, Dane Cheasley, Ian Campbell, David D.L. Bowtell, and Elizabeth L. Christie. 2021. "Phenotypic Consequences of SLC25A40-ABCB1 Fusions beyond Drug Resistance in High-Grade Serous Ovarian Cancer" Cancers 13, no. 22: 5644. https://doi.org/10.3390/cancers13225644

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