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

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.

New Insights into Chemoresistance Mediated by Mdm2 Inhibitors: The Benefits of Targeted Therapy over Common Cytostatics

“…The findings suggest that paclitaxel insensitivity is associated with the overexpression of both ABCB1 (MDR1) and ABCG2 (BCRP) transporters. This result, on the one hand, is consistent with the literature data [ 46 , 47 ], and on the other, it emphasizes the urgent need to expand the range of efflux proteins studied, compared with the recent idea of P-glycoprotein as the main source of resistance.…”

Organoids in ovarian cancer: a platform for disease modeling, precision medicine, and drug assessment

“…McCorkle et al cultured seven PDO lines from tumor tissues of seven OC patients. RNA sequencing was then performed to analyze the differences in gene expression between the paclitaxel-sensitive and -resistant organoids, revealing a significant upregulation of the ABCB1 gene in the resistant organoids (McCorkle et al 2021 ). Sun et al established ten PDOs from four platinum-resistant and six platinum-sensitive OC patients’ tumor tissues and identified Aurora-A as a resistant target through RNA sequencing analysis (Sun et al 2020 ).…”

Current insights into the oncogenic roles of lncRNA LINC00355

“…Studies have shown that some other LINC00355 downstream targets promote chemotherapy resistance in cancer. For example, HMGA2 promotes cisplatin resistance in CRC and CC [ 69 , 70 ] and oxaliplatin resistance in CRC [ 71 ]; ABCB1 promotes erastin, docetaxel, and paclitaxel resistance in OC [ 72 , 73 ]; ITGA2 promotes paclitaxel resistance in OC [ 74 ]; WNT10B promotes doxorubicin resistance in TNBC [ 75 ] and cisplatin resistance in CRC [ 76 ]; and CCNE1 promotes platinum resistance in epithelial ovarian cancer, ovarian cancer, and endometrial cancer [ 77 , 78 ].…”