Factors Influencing the Central Nervous System Distribution of a Novel Phosphoinositide 3-Kinase/Mammalian Target of Rapamycin Inhibitor GSK2126458: Implications for Overcoming Resistance with Combination Therapy for Melanoma Brain Metastases

• Published in: The Journal of pharmacology and experimental therapeutics 2016-02, Vol.356 (2), p.251-259
• Main Authors: Vaidhyanathan, Shruthi, Wilken-Resman, Brynna, Ma, Daniel J, Parrish, Karen E, Mittapalli, Rajendar K, Carlson, Brett L, Sarkaria, Jann N, Elmquist, William F
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Combined Chemotherapy Protocols; Brain - drug effects; Brain - metabolism; Brain Neoplasms - drug therapy; Brain Neoplasms - metabolism; Dogs; Drug Resistance, Neoplasm - drug effects; Drug Resistance, Neoplasm - physiology; Female; Madin Darby Canine Kidney Cells; Male; Melanoma - drug therapy; Melanoma - metabolism; Metabolism, Transport, and Pharmacogenomics; Mice; Mice, Knockout; Mice, Nude; Phosphatidylinositol 3-Kinases - metabolism; Phosphoinositide-3 Kinase Inhibitors; Quinolines - metabolism; Quinolines - pharmacology; Quinolines - therapeutic use; Sulfonamides - metabolism; Sulfonamides - pharmacology; Sulfonamides - therapeutic use; TOR Serine-Threonine Kinases - antagonists & inhibitors; TOR Serine-Threonine Kinases - metabolism
• ISSN: 1521-0103; 0022-3565; 1521-0103
• DOI: 10.1124/jpet.115.229393

Small molecule inhibitors targeting the mitogen-activated protein kinase pathway (Braf/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase) have had success in extending survival for patients with metastatic melanoma. Unfortunately, resistance may occur via cross-activation of alternate signaling pathways. One approach to overcome resistance is to simultaneously target the phosphoinositide 3-kinase/mammalian target of rapamycin signaling pathway. Recent reports have shown that GSK2126458 [2,4-difluoro-N-(2-methoxy-5-(4-(pyridazin-4-yl)quinolin-6-yl)pyridin-3-yl) benzenesulfonamide], a dual phosphoinositide 3-kinase/mammalian target of rapamycin inhibitor, can overcome acquired resistance to Braf and mitogen-activated protein kinase kinase inhibitors in vitro. These resistance mechanisms may be especially important in melanoma brain metastases because of limited drug delivery across the blood-brain barrier. The purpose of this study was to investigate factors that influence the brain distribution of GSK2126458 and to examine the efficacy of GSK2126458 in a novel patient-derived melanoma xenograft (PDX) model. Both in vitro and in vivo studies indicate that GSK2126458 is a substrate for P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp), two dominant active efflux transporters in the blood-brain barrier. The steady-state brain distribution of GSK2126458 was 8-fold higher in the P-gp/Bcrp knockout mice compared with the wild type. We also observed that when simultaneously infused to steady state, GSK212658, dabrafenib, and trametinib, a rational combination to overcome mitogen-activated protein kinase inhibitor resistance, all had limited brain distribution. Coadministration of elacridar, a P-gp/Bcrp inhibitor, increased the brain distribution of GSK2126458 by approximately 7-fold in wild-type mice. In the PDX model, GSK2126458 showed efficacy in flank tumors but was ineffective in intracranial melanoma. These results show that P-gp and Bcrp are involved in limiting the brain distribution of GSK2126458 and provide a rationale for the lack of efficacy of GSK2126458 in the orthotopic PDX model.