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Efficacy of osimertinib against EGFRvIII+ glioblastoma.

TitleEfficacy of osimertinib against EGFRvIII+ glioblastoma.
Publication TypeJournal Article
Year of Publication2020
AuthorsChagoya G, Kwatra SG, Nanni CW, Roberts CM, Phillips SM, Nullmeyergh S, Gilmore SP, Spasojevic I, Corcoran DL, Young CC, Ballman KV, Ramakrishna R, Cross DA, Markert JM, Lim M, Gilbert MR, Lesser GJ, Kwatra MM
JournalOncotarget
Volume11
Issue22
Pagination2074-2082
Date Published2020 Jun 02
ISSN1949-2553
Abstract

Epidermal Growth Factor Receptor variant III (EGFRvIII) is an active mutant form of EGFR that drives tumor growth in a subset of glioblastoma (GBM). It occurs in over 20% of GBMs, making it a promising receptor for small molecule targeted therapy. We hypothesize that poor penetration of the blood-brain barrier by previously tested EGFR-tyrosine kinase inhibitors (EGFR-TKIs) such as afateninb, erlotinib, gefitinib, and lapatinib played a role in their limited efficacy. The present study examined the effects of osimertinib (previously known as AZD9291) on EGFRvIII+ GBM models, both and . Therefore, a panel of six GBM stem cells (GSCs) expressing EGFRvIII+ was evaluated. The EGFRvIII+ GSC differed in the expression of EGFRvIII and other key genes. The GSC line D317, which expresses high levels of EGFRvIII and has robust tyrosine kinase activity, was selected for assessing osimertinib's efficacy. Herein, we report that osimertinib inhibits the constitutive activity of EGFRvIII tyrosine kinase with high potency (<100 nM) while also inhibiting its downstream signaling. Further, osimertinib inhibited D317's growth and in both heterotopic and orthotopic xenograft models. Additional preclinical studies are warranted to identify EGFRvIII+ GBM's molecular signature most responsive to osimertinib.

DOI10.18632/oncotarget.27599
Alternate JournalOncotarget
PubMed ID32547705
PubMed Central IDPMC7275784
Grant ListUH2 TR001370 / TR / NCATS NIH HHS / United States
Division: 
Biostatistics
Category: 
Faculty Publication