WSD-0922, a novel brain-penetrant inhibitor of epidermal growth factor receptor, promotes survival in glioblastoma mouse models

Jason E. Conage-Pough, Sylwia A. Stopka, Ju Hee Oh, Ann C. Mladek, Danielle M. Burgenske, Michael S. Regan, Gerard Baquer, Paul A. Decker, Brett L. Carlson, Katrina K. Bakken, Jinqiang Zhang, Lily Liu, Claire Sun, Zhihua Mu, Wei Zhong, Nhan L. Tran, William F. Elmquist, Nathalie Y.R. Agar, Jann N. Sarkaria, Forest M. White

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Background: Although the epidermal growth factor receptor (EGFR) is a frequent oncogenic driver in glioblastoma (GBM), efforts to therapeutically target this protein have been largely unsuccessful. The present preclinical study evaluated the novel EGFR inhibitor WSD-0922. Methods: We employed flank and orthotopic patient-derived xenograft models to characterize WSD-0922 and compare its efficacy to erlotinib, a potent EGFR inhibitor that failed to provide benefit for GBM patients. We performed long-term survival studies and collected short-term tumor, plasma, and whole-brain samples from mice treated with each drug. We utilized mass spectrometry to measure drug concentrations and spatial distribution and to assess the impact of each drug on receptor activity and cellular signaling networks. Results: WSD-0922 inhibited EGFR signaling as effectively as erlotinib in in vitro and in vivo models. While WSD-0922 was more CNS penetrant than erlotinib in terms of total concentration, comparable concentrations of both drugs were measured at the tumor site in orthotopic models, and the concentration of free WSD-0922 in the brain was significantly less than the concentration of free erlotinib. WSD-0922 treatment provided a clear survival advantage compared to erlotinib in the GBM39 model, with marked suppression of tumor growth and most mice surviving until the end of the study. WSD-0922 treatment preferentially inhibited phosphorylation of several proteins, including those associated with EGFR inhibitor resistance and cell metabolism. Conclusions: WSD-0922 is a highly potent inhibitor of EGFR in GBM, and warrants further evaluation in clinical studies.

Original languageEnglish (US)
Article numbervdad066
JournalNeuro-Oncology Advances
Volume5
Issue number1
DOIs
StatePublished - Jan 1 2023

Bibliographical note

Publisher Copyright:
© 2023 The Author(s). Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.

Keywords

  • EGFR
  • WSD-0922
  • blood-brain barrier
  • erlotinib
  • glioblastoma

PubMed: MeSH publication types

  • Journal Article

Fingerprint

Dive into the research topics of 'WSD-0922, a novel brain-penetrant inhibitor of epidermal growth factor receptor, promotes survival in glioblastoma mouse models'. Together they form a unique fingerprint.

Cite this