Everolimus improves the efficacy of dasatinib in PDGFRα-driven glioma
Zachary Miklja, … , Bernard L. Marini, Carl Koschmann
Zachary Miklja, … , Bernard L. Marini, Carl Koschmann
Published June 30, 2020
Citation Information: J Clin Invest. 2020;130(10):5313-5325. https://doi.org/10.1172/JCI133310.
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Everolimus improves the efficacy of dasatinib in PDGFRα-driven glioma

Abstract

Pediatric and adult high-grade gliomas (HGGs) frequently harbor PDGFRA alterations. We hypothesized that cotreatment with everolimus may improve the efficacy of dasatinib in PDGFRα-driven glioma through combinatorial synergism and increased tumor accumulation of dasatinib. We performed dose-response, synergism, P-glycoprotein inhibition, and pharmacokinetic studies in in vitro and in vivo human and mouse models of HGG. Six patients with recurrent PDGFRα-driven glioma were treated with dasatinib and everolimus. We found that dasatinib effectively inhibited the proliferation of mouse and human primary HGG cells with a variety of PDGFRA alterations. Dasatinib exhibited synergy with everolimus in the treatment of HGG cells at low nanomolar concentrations of both agents, with a reduction in mTOR signaling that persisted after dasatinib treatment alone. Prolonged exposure to everolimus significantly improved the CNS retention of dasatinib and extended the survival of PPK tumor–bearing mice (mutant TP53, mutant PDGFRA, H3K27M). Six pediatric patients with glioma tolerated this combination without significant adverse events, and 4 patients with recurrent disease (n = 4) had a median overall survival of 8.5 months. Our results show that the efficacy of dasatinib treatment of PDGFRα-driven HGG was enhanced with everolimus and suggest a promising route for improving targeted therapy for this patient population.

Authors

Zachary Miklja, Viveka Nand Yadav, Rodrigo T. Cartaxo, Ruby Siada, Chase C. Thomas, Jessica R. Cummings, Brendan Mullan, Stefanie Stallard, Alyssa Paul, Amy K. Bruzek, Kyle Wierzbicki, Tao Yang, Taylor Garcia, Ian Wolfe, Marcia Leonard, Patricia L. Robertson, Hugh J.L. Garton, Daniel R. Wahl, Hemant Parmar, Jann N. Sarkaria, Cassie Kline, Sabine Mueller, Theodore Nicolaides, Chana Glasser, Sarah E.S. Leary, Sriram Venneti, Chandan Kumar-Sinha, Arul M. Chinnaiyan, Rajen Mody, Manjunath P. Pai, Timothy N. Phoenix, Bernard L. Marini, Carl Koschmann

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Figure 2

Addition of everolimus provides synergism and strong P-gp blockade.

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Addition of everolimus provides synergism and strong P-gp blockade. (A) ...
(A) Viability of IUE HGG neurospheres in response to various combinations of dasatinib and everolimus. n = 3 technical replicates. (B) Western blot analysis of p-PDGFRα/β (Tyr849/Tyr857), p-Src (Tyr416), and p-S6 (Ser235–236) expression in PDGFRA-amplified mouse HGG cells treated with dasatinib or everolimus monotherapy or with coadministration of dasatinib and everolimus. In the coadministration condition, the drugs were administered at equal doses (doses are indicated at the top of the figure). CTRL, control. (C) Quantification of Western blot analysis for the mouse HGG cell line (PPK) and a human PDGFRA-enhanced cell line (XIII-P), demonstrating a greater reduction in p-S6 expression with coadministration of dasatinib and everolimus than with either drug alone at 0.1 μM in the mouse cell line and at all administered doses in the human cell line. (D) A limiting dilution assay was performed on IUE PPK neurospheres treated with either 1 μM or 10 μM doses of dasatinib or everolimus, or dasatinib and everolimus together (5 μM). n = 3 technical replicates. (E) Everolimus and dasatinib synergism CI assessment. (F) Plot of P-gp inhibition using an in vitro assay with controls (higher numbers = greater P-gp inhibition) shows higher P-gp inhibition with the 1 μM everolimus dose condition than with the negative control or no treatment conditions ( **P = 0.0045 and ****P ≤ 0.0001, by Tukey’s multiple comparisons test, respectively). Neg., negative; Pos., positive. Data represent the mean ± SEM (A, D, and F).