Research Papers:
Efficacy of osimertinib against EGFRvIII+ glioblastoma
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Abstract
Gustavo Chagoya8,*, Shawn G. Kwatra5,6,*, Cory W. Nanni1, Callie M. Roberts1, Samantha M. Phillips9, Sarah Nullmeyergh3, Samuel P. Gilmore1, Ivan Spasojevic4, David L. Corcoran2, Christopher C. Young1, Karla V. Ballman10, Rohan Ramakrishna11, Darren A. Cross12, James M. Markert8, Michael Lim7, Mark R. Gilbert13, Glenn J. Lesser14 and Madan M. Kwatra1,3,4
1 Departments of Anesthesiology, Duke University Medical Center, Durham, NC, USA
2 Genomic and Computational Biology, Duke University Medical Center, Durham, NC, USA
3 Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, USA
4 Duke Cancer Institute, Duke University Medical Center, Durham, NC, USA
5 Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University School of Medicine, Baltimore, MD, USA
6 Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
7 Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
8 Department of Neurosurgery, The University of Alabama at Birmingham, Birmingham, AL, USA
9 Tri-Institutional MD-PhD Program, Weill Cornell Medical College, The Rockefeller University, Memorial Sloan Kettering Cancer Institute, New York, NY, USA
10 Department of Healthcare Policy and Research, Weill Cornell Medicine, New York, NY, USA
11 Department of Surgery, Weill Cornell Medicine, New York, NY, USA
12 IMED Oncology, Global Medical Affairs, AstraZeneca, Cambridge, UK
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
* These authors contributed equally to this work
Correspondence to:
| Madan M. Kwatra, | email: | [email protected] |
Keywords: EGFRvIII; tyrosine kinase; glioblastoma stem cells; osimertinib; xenografts
Received: February 10, 2020 Accepted: April 27, 2020 Published: June 02, 2020
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.
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