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 FRtargeting 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-gpmediated 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.

Pre-clinical evaluation of EC1456, a folate-tubulysin anti-cancer therapeutic

“…NCI-ADR cells, which are a known high P-gp expressing cell line, were used as a positive control, albeit at one fourth of the protein concentration as the other cells. This overexpression of P-gp in KB-PR10 cells also caused them to be cross-resistant (IC 50 > 1 μM) to vintafolide, which was expected 27 . The low P-gp expressing KB and KB-CR2000 cells remained sensitive (IC 50 of 5–9 nM) to vintafolide.…”

Bi-specific ligand-controlled chimeric antigen receptor T-cell therapy for non-small cell lung cancer

“…In contrast, the low to negligible distribution of FRα in normal human tissues is restricted to the apical (luminal) surface of cells, which reside in the bronchial epithelium, renal tubules and choroid plexus (13,14). Consequently, six folate-targeted drugs are currently undergoing human clinical trials (15)(16)(17)(18)(19), and one folate-vinca alkaloid conjugate (EC145) has even advanced to phase IIb clinical trials for targeted therapy of NSCLC (18,19). Thus, FRα has not only become an established NSCLC marker, but it could also act as a promising target for adoptive CAR-T therapy for this cancer.…”

Phase I/II clinical trial of the targeted chemotherapeutic drug, folate-tubulysin, in dogs with naturally-occurring invasive urothelial carcinoma

“…Subsequently, a phase I trial demonstrated an acceptable safety profile of vintafolide in people receiving this drug for an assortment of solid tumors [8]. Varying degrees of clinical effectiveness were observed in phase II and III trials, with the greatest benefit noted in patients with tumors with the highest FR expression and tumors lacking P-glycoprotein expression [2, 3, 5, 9]. These findings were encouraging for future targeting of FRs, but also indicated the need for additional, potentially more active drug conjugates.…”