Genetic Analysis of EGFRvIII-independent Glioblastoma Maintenance

Ludwig Institute For Cancer Res Ltd, La Jolla CA

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Abstract

DESCRIPTION (provided by applicant): Amplification and mutation of the epidermal growth factor receptor (EGFR) gene are common genetic hallmarks of glioblastoma multiforme (GBM). The most common mutation is an in-frame deletion of exons 2-7, resulting in a constitutively active variant of the receptor, EGFRvIII/ EGFR (herein refered to as EGFR). Therapies that target EGFR and EGFR, such as small molecule tyrosine kinase inhibitors (TKIs), are currently in clinical trials for the treatment of GBM. However, their efficacy has been limited due to both upfront and acquired drug resistance. Thus, it seems that blocking these molecules alone may not sufficiently translate into a clinical benefit for GBM patients. Using a genetic model of tetracycline-regulated EGFR expression, the lab previously demonstrated that this receptor is esential for the maintenance of glioma growth in vivo. However, similar to a clinical situation of acquired drug resistance, some tumors eventually regained aggressive growth after a period of stasis. Surprisingly, these breakthrough tumors persisted despite sustained suppression of EGFR, were substantially more resistant to apoptosis compared to EGFR-dependent tumors, and cell lines generated from these tumors were resistant to EGFR TKIs even when EGFR was re- expressed. Gene expression profiles of EGFR-independent cell lines generated using microarray technology revealed that a number of genes were significantly up-regulated compared to EGFR-dependent cell lines. To identify likely candidates that may be responsible for EGFR-independent in vivo growth and maintenance, the array data was screened using the following criteria: (1) clinical relevance in GBM, (2) association with decreased apoptosis and disease, and (3) drug-targetable. From this screen, the focus was directed toward two apoptosis-related genes: Aurora kinase A (AURKA) and Clusterin (CLU). The proposed project aims to test the hypothesis that an anti-apoptotic expression signature unique to the EGFR-independent phenotype not only supports EGFR-independent tumor maintenance but may also contribute to EGFR TKI resistance. Specifically, Aim 1 wil determine the genetic requirement for EGFR-independent tumor maintenance by conducting loss of function studies. Aim 2 will determine the necessity and sufficiency of these genes to confer resistance to EGFR receptor inhibition by conducting loss of function studies in the presence of EGFR TKIs. Taken together, this study will shed light on molecular mechanisms that can serve as alternative escape routes utilized by gliomas to overcome blockade of EGFR, which wil be invaluable to the development of more effective therapies for GBM patients.