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Research ArticleMetabolism, Transport, and Pharmacogenomics

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

Shruthi Vaidhyanathan, Brynna Wilken-Resman, Daniel J. Ma, Karen E. Parrish, Rajendar K. Mittapalli, Brett L. Carlson, Jann N. Sarkaria and William F. Elmquist
Journal of Pharmacology and Experimental Therapeutics February 2016, 356 (2) 251-259; DOI: https://doi.org/10.1124/jpet.115.229393
Shruthi Vaidhyanathan
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.)
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Brynna Wilken-Resman
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.)
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Daniel J. Ma
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.)
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Karen E. Parrish
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.)
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Rajendar K. Mittapalli
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.)
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Brett L. Carlson
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.)
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Jann N. Sarkaria
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.)
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William F. Elmquist
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.)
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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.

Footnotes

    • Received September 17, 2015.
    • Accepted November 23, 2015.
  • S.V. and B.W.-R. contributed equally to this work and are co-first authors.

  • This research was supported by the National Institutes of Health National Cancer Institute [Grants R01CA138437 and P50CA108961] and the National Institutes of Health National Institute of Neurological Disorders and Stroke [Grant R01NS077921]. S.V. was supported by a Ronald J. Sawchuk Fellowship.

  • dx.doi.org/10.1124/jpet.115.229393.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 356 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 356, Issue 2
1 Feb 2016
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Research ArticleMetabolism, Transport, and Pharmacogenomics

GSK2126458 Distribution to the Brain

Shruthi Vaidhyanathan, Brynna Wilken-Resman, Daniel J. Ma, Karen E. Parrish, Rajendar K. Mittapalli, Brett L. Carlson, Jann N. Sarkaria and William F. Elmquist
Journal of Pharmacology and Experimental Therapeutics February 1, 2016, 356 (2) 251-259; DOI: https://doi.org/10.1124/jpet.115.229393

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Research ArticleMetabolism, Transport, and Pharmacogenomics

GSK2126458 Distribution to the Brain

Shruthi Vaidhyanathan, Brynna Wilken-Resman, Daniel J. Ma, Karen E. Parrish, Rajendar K. Mittapalli, Brett L. Carlson, Jann N. Sarkaria and William F. Elmquist
Journal of Pharmacology and Experimental Therapeutics February 1, 2016, 356 (2) 251-259; DOI: https://doi.org/10.1124/jpet.115.229393
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