title: 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.
abstract: 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.
authors.affiliation: Department of Pharmaceutics, Brain Barriers Research Center, University of Minnesota, Minneapolis, Minnesota (S.V., B.W.-R., K.E.P., R.K.M., W.F.E.); and Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (D.J.M, B.L.C., J.N.S.).
authors.forename: Shruthi
authors.initials: S
authors.lastname: Vaidhyanathan
authors.affiliation: Department of Pharmaceutics, Brain Barriers Research Center, University of Minnesota, Minneapolis, Minnesota (S.V., B.W.-R., K.E.P., R.K.M., W.F.E.); and Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (D.J.M, B.L.C., J.N.S.).
authors.forename: Brynna
authors.initials: B
authors.lastname: Wilken-Resman
authors.affiliation: Department of Pharmaceutics, Brain Barriers Research Center, University of Minnesota, Minneapolis, Minnesota (S.V., B.W.-R., K.E.P., R.K.M., W.F.E.); and Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (D.J.M, B.L.C., J.N.S.).
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Ma
authors.affiliation: Department of Pharmaceutics, Brain Barriers Research Center, University of Minnesota, Minneapolis, Minnesota (S.V., B.W.-R., K.E.P., R.K.M., W.F.E.); and Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (D.J.M, B.L.C., J.N.S.).
authors.forename: Karen E
authors.initials: KE
authors.lastname: Parrish
authors.affiliation: Department of Pharmaceutics, Brain Barriers Research Center, University of Minnesota, Minneapolis, Minnesota (S.V., B.W.-R., K.E.P., R.K.M., W.F.E.); and Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (D.J.M, B.L.C., J.N.S.).
authors.forename: Rajendar K
authors.initials: RK
authors.lastname: Mittapalli
authors.affiliation: Department of Pharmaceutics, Brain Barriers Research Center, University of Minnesota, Minneapolis, Minnesota (S.V., B.W.-R., K.E.P., R.K.M., W.F.E.); and Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (D.J.M, B.L.C., J.N.S.).
authors.forename: Brett L
authors.initials: BL
authors.lastname: Carlson
authors.affiliation: Department of Pharmaceutics, Brain Barriers Research Center, University of Minnesota, Minneapolis, Minnesota (S.V., B.W.-R., K.E.P., R.K.M., W.F.E.); and Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (D.J.M, B.L.C., J.N.S.).
authors.forename: Jann N
authors.initials: JN
authors.lastname: Sarkaria
authors.affiliation: Department of Pharmaceutics, Brain Barriers Research Center, University of Minnesota, Minneapolis, Minnesota (S.V., B.W.-R., K.E.P., R.K.M., W.F.E.); and Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (D.J.M, B.L.C., J.N.S.) elmqu011@umn.edu.
authors.forename: William F
authors.initials: WF
authors.lastname: Elmquist
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D004285:Dogs; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000502:physiology; D005260:Female; D061985:Madin Darby Canine Kidney Cells; D008297:Male; D008545:Melanoma / Q000188:drug therapy / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011724:Pyridazines; D011804:Quinolines / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D013449:Sulfonamides / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000096926:Benzenesulfonamides
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011724:Pyridazines; D011804:Quinolines; D013449:Sulfonamides; D058570:TOR Serine-Threonine Kinases; C561454:omipalisib; D000096926:Benzenesulfonamides