Abstract B65: High levels of expression of P-glycoprotein/multidrug resistance protein result in resistance to vintafolide

Targeting surface receptors overexpressed on cancer cells is one way to specifically treat cancer versus normal cells. Vintafolide (EC145), which consists of folate linked to a cytotoxic small molecule, desacetylvinblastine hydrazide (DAVLBH), takes advantage of the overexpression of folate receptor (FR) on cancer cells. Once bound to FR, vintafolide enters the cell by endocytosis, and the reducing environment of the endosome cleaves the linker, releasing DAVLBH to destabilize microtubules. Vintafolide has shown efficacy and improved tolerability compared to DAVLBH in FR-positive preclinical models. As the first FR-targeting drug to reach the clinic, vintafolide has achieved favorable responses in Phase II clinical trials in FR-positive ovarian and lung cancer. However, some FR-positive patients in these clinical trials do not respond to vintafolide. We sought to identify potential biomarkers of resistance to aid in the future development of this and other FR-targeting drugs. Here, we confirm in both in vitro and in vivo preclinical models that high P-glycoprotein (P-gp) expression was the strongest predictor of resistance to DAVLBH in a panel of 359 cancer cell lines. Furthermore, targeted delivery of DAVLBH via the FR as in vintafolide fails to overcome P-gp mediated efflux of DAVLBH as seen in FR-expressing engineered cell lines and in vivo models. Therefore, we suggest that patients whose tumors express high levels of P-gp be excluded from future clinical trials for vintafolide as well as other FR-targeted therapeutics bearing a P-gp substrate. Citation Format: Amy D. Guertin, Jennifer O9Neil, Alexander Stoeck, Joseph A. Reddy, Razvan Cristescu, Brian B. Haines, Marlene C. Hinton, Ryan Dorton, Alicia Bloomfield, Melissa Nelson, Marilynn Vetzel, Serguei Lejnine, Michael Nebozhyn, Theresa Zhang, Andrey Loboda, Kristen L. Picard, Emmett V. Schmidt, Isabelle Dussault, Christopher P. Leamon. High levels of expression of P-glycoprotein/multidrug resistance protein result in resistance to vintafolide. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B65.