Abstract 782: Development of folate receptor positive drug-resistant cell lines and strategies to overcome drug resistance

Abstract

Abstract In support of our clinical strategy to treat folate receptor (FR)-positive platinum resistant ovarian cancer patients with the folate desacetylvinblastine (DAVLBH) conjugate, EC145, we created two FR-expressing DAVLBH resistant cell lines (named KB-DR and NCI/ADR-FR). Results from a calcein efflux assay confirmed that the KB-DR and NCI/ADR-FR cell lines both express high levels of an efflux pump, and subsequent flow cytometry analysis using an anti-p-glycoprotein (pgp) antibody (MRK-16) confirmed pgp overexpression. As predicted, these DAVLBH-resistant cell lines were also less sensitive to single agent EC145. However, when tested in combination with known pgp inhibitors, such as lapatinib or verapamil, substantially enhanced cell killing activity was observed. Furthermore, folate conjugates of non-pgp substrates, such as folate-tubulysin and a folate-epothilone, were also found to be highly active against these drug-resistant cell lines. In subsequent studies, we created a cisplatin resistant cell line (named KB-CR) and found that it remained just as susceptible to EC145 as the parent KB cells, suggesting that cisplatin-resistance did not affect FR function or sensitivity to folate-targeted microtubule inhibitors. Since the development of drug resistance did not appear to alter the function or exploitability of the FR, these new models will be useful for testing novel folate-targeted strategies for the treatment of difficult-to-treat cancers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 782. doi:1538-7445.AM2012-782