Abstract A50: Lapatinib potentiates the antitumor effects of paclitaxel treatment in resistant ovarian cancer cells

Abstract

Abstract Introduction: Frontline treatment regimens for ovarian cancer routinely consist of repeated cycles of paclitaxel/platinum doublets; however, chemotherapy resistance frequently leads to recurrent or refractory disease. Novel therapeutic strategies aimed at circumventing or preventing resistance are needed for improved disease control. Experimental Procedures: Multiple paclitaxel-resistant ovarian cancer cell line models were established via repeated cycles of paclitaxel treatment in vitro. Resistance to paclitaxel was assessed using dose response cell viability assays with CellTiter-Glo 2.0 and calculation of IC50 values using a 4-parameter logistic regression model. RNAseq and whole-exome sequencing were used to examine genomic variation distinguishing resistant lines from their sensitive counterparts. Recurrent expression differences associated with paclitaxel resistance were identified, a subset of which were selected for further validation. Candidate genes and pathways associated with paclitaxel resistance were manipulated using siRNA and/or small-molecule inhibitors and assessed for the ability to alter the resistant phenotype. Synergistic interactions for drug combinations were evaluated using the Loewe Additivity model. Results: Paclitaxel-resistant ovarian cancer cell lines were derived from TOV-21G, OVCAR-3, and UWB1.289 cells. Resistant cell lines exhibited increases in paclitaxel IC50 ranging from 6.5 to 94-fold over their parental control cells. RNAseq analysis identified the transcript encoding P-glycoprotein (P-gp), ABCB1, among the most highly upregulated genes in the resistant TOV-21G and OVCAR-3 cells while no such induction of expression was seen in resistant UWB1.289 cells. Previous reports have shown several different tyrosine kinase inhibitors (e.g., lapatinib, neratinib, dasatinib, etc.) have the ability to inhibit P-gp function. We tested a panel of tyrosine kinase inhibitors for the ability to sensitize resistant P-gp-overexpressing ovarian cancer cells to paclitaxel. The most potent synergistic antiproliferative activity was observed when lapatinib was combined with paclitaxel treatment of resistant TOV-21G and OVCAR-3 cells; however, a similar interaction was not observed in resistant UWB1.289 cells that do not overexpress P-gp. The dependence of this synergistic effect on P-gp expression was confirmed by using siRNA to inhibit P-gp expression in paclitaxel-resistant TOV-21G and OVCAR-3 cells, significantly reducing paclitaxel IC50 by 20.7 and 6.2-fold, respectively, and eliminating cytotoxic synergy. Conclusions: Paclitaxel and lapatinib have synergistic anticancer properties when used to treat P-gp-overexpressing ovarian cancer cells. The addition of lapatinib to second-line dose-dense paclitaxel therapy could be an effective strategy for a subset of ovarian cancer patients with recurrent disease and warrants further clinical exploration. Citation Format: Rob McCorkle, Justin W. Gorski, Abigail Anderson, Jill M. Kolesar. Lapatinib potentiates the antitumor effects of paclitaxel treatment in resistant ovarian cancer cells [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr A50.