Objective: This study aimed to dissect the dynamic regulation of ATP-binding cassette (ABC) transporters across early (acute) and late (chronic) phases of chemotherapy exposure in ovarian cancer cells to uncover efflux-mediated mechanisms that enable the emergence and stabilization of drug resistance. Hypothesis: We hypothesized that chemoresistance is not governed solely by ABCB1 but rather arises from a flexible system involving a multi-transporter efflux network integrated with metabolic reprogramming. Methods: We profiled five clinically relevant ABC transporters (ABCB1, ABCA8, ABCG2, ABCB5, and CFTR) -selected based on evidence from our collaborative network and ovarian cancer patient cohorts across four ovarian carcinoma cell lines (OVCAR8, OVCAR3, OV90, and TOV21G) using quantitative RT-PCR. Cell viability assays were used to determine half-maximal inhibitory concentrations (IC50) with 48 and 72 h of paclitaxel and cisplatin exposure. Models of acquired resistance were generated using continuous chemotherapy exposure followed by a 2-4-week recovery period to allow stabilization of resistant phenotypes. Resistant cells were then evaluated by re-profiling IC 50 shifts and ABC transporter expression. Additionally, bioinformatic analysis of publicly available RNA-sequencing datasets was performed to characterize transporter shifts and regulatory factors during the transition from sensitive to resistant states. Result: In our in-vitro models, paclitaxel exposure triggered robust ABCB1 upregulation, while other understudied ABC transporters showed significant dysregulation during both early adaptive and stabilized resistant phases under paclitaxel and cisplatin treatment. Secondary analysis of publicly available RNA-sequencing datasets further identified transcriptomic signatures consistent with the simultaneous induction of multiple ABC transporter genes in chemo-resistant phenotypes. Conclusions: Our analyses confirmed ABCB1 as a principal driver of paclitaxel resistance in high-grade serous ovarian cancer. However, we also identified upregulation of several other transporters, indicating resistance arises from a network of multiple drug transporters. These data support that chemoresistance is polygenic and system-level, not dependent on a single gene. In addition to ABCB1, the study revealed involvement of ABCA8, ABCG2, and ABCB5, thereby identifying new targets for therapeutic strategies aimed at disrupting multidrug resistance in ovarian cancer. The research was carried out at the University of Iowa College of Pharmacy. The presenting author is supported by the University of Iowa Center for Biocatalysis and Bioprocessing (CBB) Graduate Fellowship. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
Chakrabortty et al. (Fri,) studied this question.