Journal article
Lapatinib and poziotinib overcome ABCB1-mediated paclitaxel resistance in ovarian cancer
PloS one, Vol.16(8), e0254205
08/04/2021
DOI: 10.1371/journal.pone.0254205
PMCID: PMC8336885
PMID: 34347777
Abstract
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.
Details
- Title: Subtitle
- Lapatinib and poziotinib overcome ABCB1-mediated paclitaxel resistance in ovarian cancer
- Creators
- J Robert McCorkle - University of KentuckyJustin W Gorski - University of KentuckyJinpeng Liu - University of KentuckyMcKayla B Riggs - University of KentuckyAnthony B McDowell - University of KentuckyNan Lin - University of KentuckyChi Wang - University of KentuckyFrederick R Ueland - University of KentuckyJill M Kolesar - University of Kentucky
- Resource Type
- Journal article
- Publication Details
- PloS one, Vol.16(8), e0254205
- DOI
- 10.1371/journal.pone.0254205
- PMID
- 34347777
- PMCID
- PMC8336885
- ISSN
- 1932-6203
- eISSN
- 1932-6203
- Grant note
- T32 CA160003 / NCI NIH HHS P30 CA177558 / NCI NIH HHS
- Language
- English
- Date published
- 08/04/2021
- Academic Unit
- Pharmacy; Pharmaceutical Sciences and Experimental Therapeutics
- Record Identifier
- 9984695787602771
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