Efficacy of osimertinib against EGFRvIII+ glioblastoma.

Gustavo Chagoya,Rohan Ramakrishna,Glenn J Lesser,Darren A Cross,Callie M Roberts,James M Markert,Sarah Nullmeyergh,Karla V Ballman,Samantha M Phillips,Shawn G Kwatra,Cory W Nanni,Michael Lim,David L Corcoran,Samuel P Gilmore,Ivan Spasojevic,Mark R Gilbert,Christopher C Young,Madan M Kwatra

doi:10.18632/oncotarget.27599

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 in vitro and in vivo. 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 in vitro and in both heterotopic and orthotopic xenograft models. Additional preclinical studies are warranted to identify EGFRvIII+ GBM’s molecular signature most responsive to osimertinib.

Highlights

Glioblastoma (GBM) is the most common and deadliest primary brain tumor
To provide additional evidence of heterogeneity of EGFRvIII+ GBMs, we examined the expression of several key genes using qPCR
Evaluation of osimertinib’s efficacy against EGFRvIII+ GBMs with high expression of EGFRvIII and a robust EGFRvIII tyrosine kinase activity revealed that osimertinib inhibits the growth of these tumors effectively

Summary

Introduction

Glioblastoma (GBM) is the most common and deadliest primary brain tumor. It carries a median survival of 16 months for newly-diagnosed patients whose treatment aligns with the current standard of care consisting of maximal safe resection followed by radiation and chemotherapy [1]. This treatment regimen improves overall survival, the benefit is modest and highlights the need for novel targeted therapies based on molecular classification. The Cancer Genome Atlas (TCGA) program recently performed the largest molecular characterization study of primary GBM tumors to date, using samples from over 500 patients [2, 3]. Several point mutations in the receptor’s extracellular and intracellular domains have been documented [2]

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Results

Conclusion