Oncogenic EGFR signaling cooperates with loss of tumor suppressor gene functions in gliomagenesis

Abstract

Glioblastoma multiforme (GBM) is a highly lethal brain tumor for which little treatment is available. The epidermal growth factor receptor (EGFR) signaling pathway is thought to play a crucial role in GBM pathogenesis, initiating the early stages of tumor development, sustaining tumor growth, promoting infiltration, and mediating resistance to therapy. The importance of this pathway is highlighted in the fact that EGFR is mutationally activated in over 50% of GBM tumors. Consistent with this, we show here that concomitant activation of wild-type and/or mutant (vIII) EGFR and ablation of Ink4A/Arf and PTEN tumor suppressor gene function in the adult mouse central nervous system generates a fully penetrant, rapid-onset high-grade malignant glioma phenotype with prominent pathological and molecular resemblance to GBM in humans. Studies of the activation of signaling events in these GBM tumor cells revealed notable differences between wild-type and vIII EGFR-expressing cells. We show that wild-type EGF receptor signals through its canonical pathways, whereas tumors arising from expression of mutant EGFR vIII do not use these same pathways. Our findings provide critical insights into the role of mutant EGFR signaling function in GBM tumor biology and set the stage for testing of targeted therapeutic agents in the preclinical models described herein. glioblastoma ͉ mouse model ͉ receptor tyrosine kinase ͉ mTORC1/2 ͉ STAT3 G lioblastoma multiforme is the most common and lethal primary malignant cancer of the central nervous system (CNS). Despite multimodal therapies, the median survival of GBM patients is Ϸ1 year. The deadly nature of GBMs resides in their explosive growth characteristic, extreme invasive behavior, and intrinsic resistance to current therapies. Despite efforts to develop novel treatments, little improvement in overall survival or progression-free survival has been achieved in the past 5 decades, reflecting an unmet need in the treatment of this cancer (1). Personalized medicine based on targeting essential molecular mechanisms for GBM survival offers an alternative therapeutic strategy.Over the years, our knowledge of GBM biology has steadily improved. From a molecular standpoint, GBMs are a highly heterogeneous tumor with multiple signaling pathways differentially activated or silenced with converging and parallel complex interactions (2). It is these intricacies that are thought to confer GBM with its notorious plasticity in response to therapeutic interventions. Therefore, a major challenge in the clinic is to determine the appropriate events to target. The most common genetic abnormality in GBMs is the activation of receptor tyrosine kinases (RTKs), of which, aberrant expression of EGFR is the most frequent (2). Concomitant with EGFR gene amplification events is the occurrence of an intragenic in-frame deletion of exons 2Ϫ7 of the EGFR gene. This rearrangement product, known as EGFRvIII, codes for a ligandindependent receptor, which is constitutively activated and highly oncogenic (reviewed in ref....

A mathematical framework to determine the temporal sequence of somatic genetic events in cancer

“…These data suggest that glial progenitor cells may tolerate full EGFR activation only after inactivation of p16 or PTEN. This result agrees with the fact that EGFR overexpression is insufficient for tumorigenesis in mouse models of glioblastoma (27,28), providing support for the temporal order of events predicted by RESIC.…”

miR-7 inhibits glioblastoma growth by simultaneously interfering with the PI3K/ATK and Raf/MEK/ERK pathways

“…AKT, a major PI3K effector, regulates the cell cycle and cell proliferation through its direct action on the cyclindependent kinase inhibitors p21 and p27, and its indirect effect on the levels of cyclin D1 and p53, as well as cell survival, through direct inhibition of pro-apoptotic signals such as Bad and the Forkhead family of transcription factors (39,40). Our data show that miR-7 expression reduces AKT2 and MEK1/2 phosphorylation levels, as well as cyclin D1 expression.…”

PDGFRA gene rearrangements are frequent genetic events in PDGFRA-amplified glioblastomas

“…Expression of constitutively active versions of EGFR by themselves does not form gliomas in experimental mouse models; these mutations must be combined with additional genetic lesions, such as Ink4/Arf deletion, for EGFR-induced glioma formation (Holland et al 1998;Zhu et al 2009). Moreover, all GBMs with EGFR gene rearrangement have amplified wild-type EGFR genes as well, suggesting that the wild-type allele of EGFR may contribute to the oncogenic effect of the mutant allele (Mellinghoff et al 2005).…”