Time-Dependent Regulation of the ABC Transporter Network Reveals Distinct Cisplatin- and Paclitaxel-Specific Resistance Mechanisms in Ovarian Carcinoma (Abstract ID: 231955)

Atonu Chakrabortty; Kaleb Feia; Melissa Fath; Dave Roman; Jill Kolesar; Jared M. McLendon

doi:10.1016/j.jpet.2026.103843

INTRODUCTION: Chemoresistance to platinum–taxane therapy remains the principal barrier to successful ovarian cancer treatment. While ABCB1, an ATP-dependent drug efflux transporter, has been extensively studied in the context of chemotherapy resistance, the contribution of the broader ABC transporter network remains poorly defined. We hypothesized that this resistance mechanism is not dependent on ABCB1 alone, but rather emerges from a flexible, multi-transporter system within the ABC superfamily. Our objective was to identify ABC transporters that undergo differential regulation during acute chemotherapy exposure and to determine whether these early adaptive shifts persist chronically in resistant cell populations. METHOD: To characterize chemotherapy-induced ABC transporter regulation, we assessed intrinsic drug sensitivity and transporter expression in ovarian cancer cell lines (OVCAR3, OVCAR8, OV-90, TOV-21G). Intrinsic sensitivity to cisplatin and paclitaxel was defined by 72-h IC₅₀ values calculated using four-parameter logistic modeling of cell viability assays. To capture early ABC transporter response during chemotherapeutic exposure, gene expression was quantified by qRT-PCR (2^⁻ΔΔCt; normalized to GAPDH) across a panel of ABC transporters, ABCB1, ABCG2, ABCA2, ABCA12, ABCA13, ABCB5, ABCA8, ABCC1, CFTR, and TAP1 following 48-h exposure to IC₅₀ concentrations of both drugs. To determine whether chemotherapy-induced early ABC regulation is maintained in stable resistant states, the same transporter panel was quantified by qRT-PCR in chronically resistant cells. Resistant models were generated through three treatment–recovery cycles (48 h cisplatin or paclitaxel followed by 2–4 weeks of recovery), selecting for cells that survive repeated drug exposure. RESULT: Viability assays confirmed heterogeneous cisplatin and paclitaxel sensitivity across all four cell lines, and chronic drug exposure induced resistance characterized by significant rightward shifts in IC₅₀ for both drugs. Acute and chronic chemotherapy resulted in distinct patterns of ABC transporter regulation. After 48-h paclitaxel treatment, coordinated induction was observed, with ABCB1 upregulated ~4–7-fold in OVCAR3/OVCAR8 and ~2–3-fold in OV-90, ABCG2 increased ~2–5-fold in OV-90/TOV-21G, and TAP1 increased ~3–5-fold in OV-90. Cisplatin produced a distinct response in OV-90, with ABCB1 upregulated ~8–12-fold and ABCA12, ABCA13, and ABCA2 showing ~1.5–3-fold changes, while OVCAR3 and OVCAR8 demonstrated ≤1.5-fold variation across these same transporters.ABCC1 and CFTR changed modestly (~1.5–3-fold), and ABCB5 showed limited, drug-dependent shifts. Analysis of publicly available RNA-seq datasets (TCGA-OV and independent GEO studies) further revealed multiple ABC transporters dysregulated in chemoresistant tumor states, supporting resistance as a product of broad transporter-network remodeling rather than reliance on a single efflux transporter. Importantly, the transporters ABCB1, ABCG2, ABCA12, ABCA8, ABCB5, ABCC1, CFTR, and TAP1 were prioritized for further examination based on evidence from our collaborators and validated in independent ovarian cancer patient cohorts, where altered expression of these eight genes was consistently associated with adverse clinical outcomes.

Time-Dependent Regulation of the ABC Transporter Network Reveals Distinct Cisplatin- and Paclitaxel-Specific Resistance Mechanisms in Ovarian Carcinoma (Abstract ID: 231955)

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