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. 2016 Feb;356(2):251-9.
doi: 10.1124/jpet.115.229393. Epub 2015 Nov 24.

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  1 , Brynna Wilken-Resman  1 , Daniel J Ma  1 , Karen E Parrish  1 , Rajendar K Mittapalli  1 , Brett L Carlson  1 , Jann N Sarkaria  1 , William F Elmquist  2
Affiliations

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 (V体育安卓版)

Shruthi Vaidhyanathan et al. J Pharmacol Exp Ther. 2016 Feb.

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 VSports手机版. 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. .

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Figures

Fig. 1.
Fig. 1.
Chemical structure of GSK2126458.
Fig. 2.
Fig. 2.
In vitro cellular accumulation of GSK2126458. (A) The accumulation of prazosin (prototypical Bcrp probe substrate; positive control) and GSK2126458 (2 μM) in MDCKII-WT and Bcrp1-transfected cells with and without specific Bcrp inhibitor Ko143 (0.2 μM). n = 3–6. (B) The accumulation of GSK2126458 (2 μM) and vinblastine (probe substrate for P-gp) in MDR1 cells with and without specific P-gp inhibitor LY335979 (1 μM). n = 3–6. (C and D) Intracellular accumulation of [3H]-prazosin (Bcrp probe substrate) in Bcrp1-transfected cells (C) and [3H]-vinblastine in MDR1-transfected cells (D) with increasing concentrations of GSK2126458 from 0.1 µM to 50 µM. n = 3. Data represent means ± S.D. *P < 0.05, compared with respective WT controls; ***P < 0.0001, compared with respective WT controls; †P < 0.05, compared with transfected line without inhibitor; †††P < 0.0001, compared with transfected line without inhibitor.
Fig. 3.
Fig. 3.
Brain distribution of GSK2126458 in FVB WT and Mdr1a/b−/−Bcrp1−/− mice. (A–C) Plasma (A), brain (B), and brain-to-plasma concentration ratios (C) of GSK2126458 in WT and Mdr1a/b−/−Bcrp1−/− mice after an oral dose of 10 mg/kg. Plasma and brain concentrations of GSK2126458 at 0.5,1,2, 4, 6, and 8 hours postdose were determined using LC-MS/MS. Data represent means ± S.D. n = 3 to 4. *P < 0.05, compared with WT; **P < 0.01; ***P ≤ 0.0001, compared with WT.
Fig. 4.
Fig. 4.
Steady-state distribution of GSK2126458 at 2 μg/h for 48 hours. Steady-state brain-to-plasma ratio of GSK2126458 in WT, Mdr1a/b−/−, Bcrp1−/−, and Mdr1a/b−/−Bcrp1−/− mice. GSK2126458 was delivered at a constant infusion rate of 2 µg/h for 48 hours using Alzet osmotic pumps implanted in the peritoneal cavity. Data represent means ± S.D.,= n = 3–5. *P < 0.05, compared with WT; ***P < 0.001, compared with WT. N.D., not detectable (not detected after correction for amount in brain microvessel, GSK2126458 LC- MS/MS assay lower limit of quantification = 1 ng/ml).
Fig. 5.
Fig. 5.
Steady-state distribution of GSK2126458, dabrafenib, and trametinib after 48-hour simultaneous infusion. Steady-state brain-to-plasma ratios of GSK2126458, dabrafenib, and trametinib in WT, Mdr1a/b−/−, Bcrp1−/−, and Mdr1a/b−/−Bcrp1−/− mice. GSK2126458, dabrafenib, and trametinib were simultaneously delivered at a constant rate of 1 µg/h, 2.5 µg/h, and 0.5 µg/h, respectively, for 48 hours using Alzet osmotic pumps implanted in the peritoneal cavity. Data represent means ± S.D. n = 3–5. *P < 0.05, compared with corresponding brain-to-plasma ratio in WT.
Fig. 6.
Fig. 6.
Efficacy of GSK2126458 in M12 xenograft model. (A) Tumor volume after flank implantation (means ± S.E.M.) with and without GSK2126458 (1.25 mg/kg daily). (B and C) Efficacy of GSK2126458 (1.25 mg/kg daily) in intracardiac (B) and intracranial (C) tumors. n = 6–10.
Fig. 7.
Fig. 7.
Influence of elacridar in a microemulsion formulation on the brain distribution of GSK2126458. Brain-to-plasma ratio of GSK212658 2 hours after pretreatment with either vehicle or elacridar microemulsion (10 mg/kg i.p.) and 1 hour after administration of GSK2126458 (10 mg/kg p.o.) in WT mice. Data represent means ± S.D. n = 3 to 4. **P < 0.01, compared with corresponding brain-to-plasma ratio in vehicle-treated mice.
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