Abstract A043: P-gp overexpression confers resistance to treatment with the antibody-drug conjugate mirvetuximab soravtansine

Abstract Mirvetuximab soravtansine (MIRV) is an antibody-drug conjugate (ADC) consisting of an anti-folate receptor-alpha (FOLR1) antibody linked to the microtubule-disrupting maytansinoid DM4 through a glutathione-reducible disulfide linker. It received FDA approval in 2022 for the treatment of FOLR1-positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer. Available reports showed that the efficacy of MIRV in ovarian cancer patients is short-lived, and its mechanism of resistance remains uncertain. To evaluate FOLR1 protein expression as a modifier of sensitivity to MIRV, we determined the surface expression of FOLR1 protein in different ovarian cancer cell lines using flow cytometry and evaluated the cytotoxic effect of MIRV in the cell lines that expressed FOLR1 differently. In addition, a recent high-throughput screen showed that most ADC cytotoxic payloads, including DM4, are substrates of the adenosine triphosphate-binding cassette (ABC) transporter genes, especially, ABCB1 (encoding the multidrug resistance protein, P-gp). ABC transporters efflux drugs from cancer cells, decreasing intracellular drug accumulation and subsequently reducing drug activity against cancer cells. To determine whether the ADC form of DM4, such as MIRV, will prevent DM4 from being recognized by P-gp as a substrate, we tested the effect of P-gp expression on the sensitivity of two non-P-gp-expressing / P-gp-expressing cell line pairs (OVCAR8 versus NCI/ADR-RES and KB-3-1 versus KB-8-5-11) to MIRV using the cell-titer glo assay. Our results show that the sensitivity of five different FOLR1-expressing ovarian cancer cell lines to MIRV is not proportionate to their FOLR1 surface expression levels, consistent with findings reported in the literature. The half maximal inhibitory concentration (IC50) of MIRV in OVCAR8, NCI/ADR-RES, KB-3-1 and KB-8-5-11 was 3.64 mcg/mL, 623.40 mcg /mL, 0.15 mcg/mL, and 1.68 mcg/mL, respectively. NCI/ADR-RES is a multidrug resistant P-gp-overexpressing cell line that is derived from the OVCAR8 human ovarian cancer cell line. KB-8-5-11 is another multidrug resistant P-gp-overexpressing cell line that is derived from the KB-3-1 human cervical cancer cell line. While the parental cell lines showed sensitivity to MIRV, the P-gp-expressing cell lines were resistant to the ADC, with the OVCAR8 / NCI/ADR-RES pair showing greater than 100-fold resistance. Clinically, the expression of ABC transporters is a relatively rare occurrence in ovarian cancer. The studied ovarian cancer cell lines did not have P-gp expression and their sensitivities to MIRV did not correlate with their FOLR1 expression levels. Further investigation of additional genetic modifiers of sensitivity to MIRV is needed to better understand how ovarian cancer and other cancer types develop resistance to the ADC. Citation Format: Omotola D. Gbadegesin, Robert W. Robey, Michael M. Gottesman. P-gp overexpression confers resistance to treatment with the antibody-drug conjugate mirvetuximab soravtansine [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr A043.