Lapatinib and poziotinib overcome ABCB1-mediated paclitaxel resistance in ovarian cancer.

Conventional frontline treatment for ovarian cancer consists of successive chemotherapy cycles of paclitaxel and platinum. Despite the initial favorable responses for most patients, chemotherapy resistance frequently leads to recurrent or refractory disease. New treatment strategies that circumvent...

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Autores principales:	J Robert McCorkle, Justin W Gorski, Jinpeng Liu, McKayla B Riggs, Anthony B McDowell, Nan Lin, Chi Wang, Frederick R Ueland, Jill M Kolesar
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/5ad0341705cb49caa5d265241a23a1bf
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spelling	oai:doaj.org-article:5ad0341705cb49caa5d265241a23a1bf2021-12-02T20:15:16ZLapatinib and poziotinib overcome ABCB1-mediated paclitaxel resistance in ovarian cancer.1932-620310.1371/journal.pone.0254205https://doaj.org/article/5ad0341705cb49caa5d265241a23a1bf2021-01-01T00:00:00Zhttps://doi.org/10.1371/journal.pone.0254205https://doaj.org/toc/1932-6203Conventional frontline treatment for ovarian cancer consists of successive chemotherapy cycles of paclitaxel and platinum. Despite the initial favorable responses for most patients, chemotherapy resistance frequently leads to recurrent or refractory disease. New treatment strategies that circumvent or prevent mechanisms of resistance are needed to improve ovarian cancer therapy. We established in vitro paclitaxel-resistant ovarian cancer cell line and organoid models. Gene expression differences in resistant and sensitive lines were analyzed by RNA sequencing. We manipulated candidate genes associated with paclitaxel resistance using siRNA or small molecule inhibitors, and then screened the cells for paclitaxel sensitivity using cell viability assays. We used the Bliss independence model to evaluate the anti-proliferative synergy for drug combinations. ABCB1 expression was upregulated in paclitaxel-resistant TOV-21G (q < 1x10-300), OVCAR3 (q = 7.4x10-156) and novel ovarian tumor organoid (p = 2.4x10-4) models. Previous reports have shown some tyrosine kinase inhibitors can inhibit ABCB1 function. We tested a panel of tyrosine kinase inhibitors for the ability to sensitize resistant ABCB1-overexpressing ovarian cancer cell lines to paclitaxel. We observed synergy when we combined poziotinib or lapatinib with paclitaxel in resistant TOV-21G and OVCAR3 cells. Silencing ABCB1 expression in paclitaxel-resistant TOV-21G and OVCAR3 cells reduced paclitaxel IC50 by 20.7 and 6.2-fold, respectively. Furthermore, we demonstrated direct inhibition of paclitaxel-induced ABCB1 transporter activity by both lapatinib and poziotinib. In conclusion, lapatinib and poziotinib combined with paclitaxel synergizes to inhibit the proliferation of ABCB1-overexpressing ovarian cancer cells in vitro. The addition of FDA-approved lapatinib to second-line paclitaxel therapy is a promising strategy for patients with recurrent ovarian cancer.J Robert McCorkleJustin W GorskiJinpeng LiuMcKayla B RiggsAnthony B McDowellNan LinChi WangFrederick R UelandJill M KolesarPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 16, Iss 8, p e0254205 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q J Robert McCorkle Justin W Gorski Jinpeng Liu McKayla B Riggs Anthony B McDowell Nan Lin Chi Wang Frederick R Ueland Jill M Kolesar Lapatinib and poziotinib overcome ABCB1-mediated paclitaxel resistance in ovarian cancer.
description	Conventional frontline treatment for ovarian cancer consists of successive chemotherapy cycles of paclitaxel and platinum. Despite the initial favorable responses for most patients, chemotherapy resistance frequently leads to recurrent or refractory disease. New treatment strategies that circumvent or prevent mechanisms of resistance are needed to improve ovarian cancer therapy. We established in vitro paclitaxel-resistant ovarian cancer cell line and organoid models. Gene expression differences in resistant and sensitive lines were analyzed by RNA sequencing. We manipulated candidate genes associated with paclitaxel resistance using siRNA or small molecule inhibitors, and then screened the cells for paclitaxel sensitivity using cell viability assays. We used the Bliss independence model to evaluate the anti-proliferative synergy for drug combinations. ABCB1 expression was upregulated in paclitaxel-resistant TOV-21G (q < 1x10-300), OVCAR3 (q = 7.4x10-156) and novel ovarian tumor organoid (p = 2.4x10-4) models. Previous reports have shown some tyrosine kinase inhibitors can inhibit ABCB1 function. We tested a panel of tyrosine kinase inhibitors for the ability to sensitize resistant ABCB1-overexpressing ovarian cancer cell lines to paclitaxel. We observed synergy when we combined poziotinib or lapatinib with paclitaxel in resistant TOV-21G and OVCAR3 cells. Silencing ABCB1 expression in paclitaxel-resistant TOV-21G and OVCAR3 cells reduced paclitaxel IC50 by 20.7 and 6.2-fold, respectively. Furthermore, we demonstrated direct inhibition of paclitaxel-induced ABCB1 transporter activity by both lapatinib and poziotinib. In conclusion, lapatinib and poziotinib combined with paclitaxel synergizes to inhibit the proliferation of ABCB1-overexpressing ovarian cancer cells in vitro. The addition of FDA-approved lapatinib to second-line paclitaxel therapy is a promising strategy for patients with recurrent ovarian cancer.
format	article
author	J Robert McCorkle Justin W Gorski Jinpeng Liu McKayla B Riggs Anthony B McDowell Nan Lin Chi Wang Frederick R Ueland Jill M Kolesar
author_facet	J Robert McCorkle Justin W Gorski Jinpeng Liu McKayla B Riggs Anthony B McDowell Nan Lin Chi Wang Frederick R Ueland Jill M Kolesar
author_sort	J Robert McCorkle
title	Lapatinib and poziotinib overcome ABCB1-mediated paclitaxel resistance in ovarian cancer.
title_short	Lapatinib and poziotinib overcome ABCB1-mediated paclitaxel resistance in ovarian cancer.
title_full	Lapatinib and poziotinib overcome ABCB1-mediated paclitaxel resistance in ovarian cancer.
title_fullStr	Lapatinib and poziotinib overcome ABCB1-mediated paclitaxel resistance in ovarian cancer.
title_full_unstemmed	Lapatinib and poziotinib overcome ABCB1-mediated paclitaxel resistance in ovarian cancer.
title_sort	lapatinib and poziotinib overcome abcb1-mediated paclitaxel resistance in ovarian cancer.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/5ad0341705cb49caa5d265241a23a1bf
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Lapatinib and poziotinib overcome ABCB1-mediated paclitaxel resistance in ovarian cancer.

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