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

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, transcripti...

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Autores principales:	Kathleen I. Pishas, 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, Elizabeth L. Christie
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	<i>ABCB1</i> high-grade serous ovarian cancer drug resistance high-throughput drug screening Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/91d80e9c900e4f8aad1cb5d9d14cd353
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spelling	oai:doaj.org-article:91d80e9c900e4f8aad1cb5d9d14cd3532021-11-25T17:02:00ZPhenotypic Consequences of <i>SLC25A40-ABCB1</i> Fusions beyond Drug Resistance in High-Grade Serous Ovarian Cancer10.3390/cancers132256442072-6694https://doaj.org/article/91d80e9c900e4f8aad1cb5d9d14cd3532021-11-01T00:00:00Zhttps://www.mdpi.com/2072-6694/13/22/5644https://doaj.org/toc/2072-6694Despite 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 <i>ABCB1</i>, 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, <i>ABCB1</i> 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 <i>ABCB1</i> fusion populations. Collectively, our findings have unraveled the underlying biology of <i>ABCB1</i> fusion-positive cells beyond drug resistance and identified novel therapeutic agents that may significantly improve the prognosis of relapsed HGSOC patients.Kathleen I. PishasKarla J. CowleyAhwan PandeyTherese HoangJessica A. BeachJennii LuuRobert VaryLorey K. SmithCarolyn E. ShembreyNineveh RashooMadelynne O. WhiteKaylene J. SimpsonAndrea BildJason I. GriffithsDane CheasleyIan CampbellDavid D. L. BowtellElizabeth L. ChristieMDPI AGarticle<i>ABCB1</i>high-grade serous ovarian cancerdrug resistancehigh-throughput drug screeningNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENCancers, Vol 13, Iss 5644, p 5644 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	<i>ABCB1</i> high-grade serous ovarian cancer drug resistance high-throughput drug screening Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	<i>ABCB1</i> high-grade serous ovarian cancer drug resistance high-throughput drug screening Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Kathleen I. Pishas 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 Elizabeth L. Christie Phenotypic Consequences of <i>SLC25A40-ABCB1</i> Fusions beyond Drug Resistance in High-Grade Serous Ovarian Cancer
description	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 <i>ABCB1</i>, 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, <i>ABCB1</i> 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 <i>ABCB1</i> fusion populations. Collectively, our findings have unraveled the underlying biology of <i>ABCB1</i> fusion-positive cells beyond drug resistance and identified novel therapeutic agents that may significantly improve the prognosis of relapsed HGSOC patients.
format	article
author	Kathleen I. Pishas 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 Elizabeth L. Christie
author_facet	Kathleen I. Pishas 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 Elizabeth L. Christie
author_sort	Kathleen I. Pishas
title	Phenotypic Consequences of <i>SLC25A40-ABCB1</i> Fusions beyond Drug Resistance in High-Grade Serous Ovarian Cancer
title_short	Phenotypic Consequences of <i>SLC25A40-ABCB1</i> Fusions beyond Drug Resistance in High-Grade Serous Ovarian Cancer
title_full	Phenotypic Consequences of <i>SLC25A40-ABCB1</i> Fusions beyond Drug Resistance in High-Grade Serous Ovarian Cancer
title_fullStr	Phenotypic Consequences of <i>SLC25A40-ABCB1</i> Fusions beyond Drug Resistance in High-Grade Serous Ovarian Cancer
title_full_unstemmed	Phenotypic Consequences of <i>SLC25A40-ABCB1</i> Fusions beyond Drug Resistance in High-Grade Serous Ovarian Cancer
title_sort	phenotypic consequences of <i>slc25a40-abcb1</i> fusions beyond drug resistance in high-grade serous ovarian cancer
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/91d80e9c900e4f8aad1cb5d9d14cd353
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Phenotypic Consequences of <i>SLC25A40-ABCB1</i> Fusions beyond Drug Resistance in High-Grade Serous Ovarian Cancer

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