Efficacy of osimertinib against EGFRvIII+ glioblastoma

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

doi:10.18632/oncotarget.27599

Efficacy of osimertinib against EGFRvIII+ glioblastoma

Oncotarget. 2020 Jun 2;11(22):2074-2082. doi: 10.18632/oncotarget.27599.

Authors

Gustavo Chagoya^#¹, Shawn G Kwatra^#^{2

3}, Cory W Nanni⁴, Callie M Roberts⁴, Samantha M Phillips⁵, Sarah Nullmeyergh⁶, Samuel P Gilmore⁴, Ivan Spasojevic⁷, David L Corcoran⁸, Christopher C Young⁴, Karla V Ballman⁹, Rohan Ramakrishna¹⁰, Darren A Cross¹¹, James M Markert¹, Michael Lim¹², Mark R Gilbert¹³, Glenn J Lesser¹⁴, Madan M Kwatra^{4

6

7}

Affiliations

¹ Department of Neurosurgery, The University of Alabama at Birmingham, Birmingham, AL, USA.
² Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
³ Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁴ Departments of Anesthesiology, Duke University Medical Center, Durham, NC, USA.
⁵ Tri-Institutional MD-PhD Program, Weill Cornell Medical College, The Rockefeller University, Memorial Sloan Kettering Cancer Institute, New York, NY, USA.
⁶ Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, USA.
⁷ Duke Cancer Institute, Duke University Medical Center, Durham, NC, USA.
⁸ Genomic and Computational Biology, Duke University Medical Center, Durham, NC, USA.
⁹ Department of Healthcare Policy and Research, Weill Cornell Medicine, New York, NY, USA.
¹⁰ Department of Surgery, Weill Cornell Medicine, New York, NY, USA.
¹¹ IMED Oncology, Global Medical Affairs, AstraZeneca, Cambridge, UK.
¹² Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹³ Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
¹⁴ Department of Internal Medicine, Section on Hematology and Oncology, Wake Forest School of Medicine, Winston-Salem, NC, USA.

^# Contributed equally.

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.

Keywords: EGFRvIII; glioblastoma stem cells; osimertinib; tyrosine kinase; xenografts.

Abstract

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