In vivo efficacy of tesevatinib in EGFR-amplified patient-derived xenograft glioblastoma models may be limited by tissue binding and compensatory signaling

Sani H. Kizilbash, Shiv K. Gupta, Karen E. Parrish, Janice K. Laramy, Minjee Kim, Gautham Gampa, Brett L. Carlson, Katrina K. Bakken, Ann C. Mladek, Mark A. Schroeder, Paul A. Decker, William F. Elmquist, Jann N. Sarkaria

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

Tesevatinib is a potent oral brain penetrant EGFR inhibitor currently being evaluated for glioblastoma therapy. Tesevatinib distribution was assessed in wild-type (WT) and Mdr1a/b (-/-)Bcrp (-/-) triple knockout (TKO) FVB mice after dosing orally or via osmotic minipump; drug-tissue binding was assessed by rapid equilibrium dialysis. Two hours after tesevatinib dosing, brain concentrations in WT and TKO mice were 0.72 and 10.03 μg/g, respectively. Brain-to-plasma ratios (Kp) were 0.53 and 5.73, respectively. With intraperitoneal infusion, brain concentrations were 1.46 and 30.6 μg/g (Kp 1.16 and 25.10), respectively. The brain-to-plasma unbound drug concentration ratios were substantially lower (WT mice, 0.03-0.08; TKO mice, 0.40-1.75). Unbound drug concentrations in brains of WT mice were 0.78 to 1.59 ng/g. In vitro cytotoxicity and EGFR pathway signaling were evaluated using EGFR-amplified patient-derived glioblastoma xenograft models (GBM12, GBM6). In vivo pharmacodynamics and efficacy were assessed using athymic nude mice bearing either intracranial or flank tumors treated by oral gavage. Tesevatinib potently reduced cell viability [IC 50 GBM12 = 11 nmol/L (5.5 ng/mL), GBM6 = 102 nmol/L] and suppressed EGFR signaling in vitro However, tesevatinib efficacy compared with vehicle in intracranial (GBM12, median survival: 23 vs. 18 days, P = 0.003) and flank models (GBM12, median time to outcome: 41 vs. 33 days, P = 0.007; GBM6, 44 vs. 33 days, P = 0.007) was modest and associated with partial inhibition of EGFR signaling. Overall, tesevatinib efficacy in EGFR-amplified PDX GBM models is robust in vitro but relatively modest in vivo, despite a high brain-to-plasma ratio. This discrepancy may be explained by drug-tissue binding and compensatory signaling.

Original languageEnglish (US)
Pages (from-to)1009-1018
Number of pages10
JournalMolecular Cancer Therapeutics
Volume20
Issue number6
DOIs
StatePublished - Jun 2021

Bibliographical note

Funding Information:
This study was supported by funding from the NCI [U54 CA 210180 (J.N. Sarkaria, W.F. Elmquist, S.H. Kizilbash); R01 CA138437 (W.F. Elmquist); K12 CA90628 (S.H. Kizilbash)]. We appreciate the help of Clinical Pharmacology Analytical Services (CPAS), College of Pharmacy, University of Minnesota, for assistance with LC/MS-MS.

Funding Information:
S.H. Kizilbash reports grants from NIH during the conduct of the study; nonfinancial support from Kadmon Corporation, grants and nonfinancial support from Orbus Therapeutics, Inc. and Apollomics, Inc., grants from Celgene, grants and nonfinancial support from Wayshine Biopharma, nonfinancial support from Calithera Biosciences, and grants and nonfinancial support from Loxo Oncology outside the submitted work. G. Gampa reports grants from NCI during the conduct of the study. J.N. Sarkaria reports grants from Basilea, Glaxo Smith Kline, Bristol-Myers Squibb, Curtana, Forma, AbbVie, Boehringer Ingelheim, Bayer, Celgene, Cible, Wayshine, Boston Scientific, AstraZeneca, Black Diamond, and Karyopharm outside the submitted work. No disclosures were reported by the other authors.

Publisher Copyright:
© 2021 American Association for Cancer Research.

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