High Levels of Expression of P-glycoprotein/Multidrug Resistance Protein Result in Resistance to Vintafolide.

Abstract

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 with 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 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 in both in vitro and in vivo preclinical 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. Mol Cancer Ther; 15(8); 1998-2008. ©2016 AACR.

• Authors: Amy D Guertin, Jennifer O'Neil, 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
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 15 Issue 8 Pg. 1998-2008 (08 2016) ISSN: 1538-8514 [Electronic] United States
• PMID: 27256377 (Publication Type: Journal Article)
• Copyright: ©2016 American Association for Cancer Research.

Chemical References

• ATP Binding Cassette Transporter, Subfamily B
• Antineoplastic Agents
• EC145
• Folate Receptors, GPI-Anchored
• RNA, Messenger
• Vinca Alkaloids
• Platinum
• Folic Acid

Topics

• ATP Binding Cassette Transporter, Subfamily B (genetics)
• Animals
• Antineoplastic Agents (pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects, genetics)
• Cluster Analysis
• Computational Biology (methods)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Drug Resistance, Neoplasm (genetics)
• Female
• Folate Receptors, GPI-Anchored (antagonists & inhibitors)
• Folic Acid (analogs & derivatives, pharmacology)
• Gene Expression
• Gene Expression Profiling
• Humans
• Mice
• Platinum (pharmacology)
• RNA, Messenger (genetics, metabolism)
• Vinca Alkaloids (pharmacology)
• Xenograft Model Antitumor Assays