Differential sensitivity of glioma- versus lung cancer-specific EGFR mutations to EGFR kinase inhibitors.

Human Oncology and Pathogenesis Program, Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Cancer Discovery (Impact Factor: 10.14). 05/2012; 2(5):458-71. DOI: 10.1158/2159-8290.CD-11-0284
Source: PubMed

ABSTRACT Activation of the epidermal growth factor receptor (EGFR) in glioblastoma (GBM) occurs through mutations or deletions in the extracellular (EC) domain. Unlike lung cancers with EGFR kinase domain (KD) mutations, GBMs respond poorly to the EGFR inhibitor erlotinib. Using RNAi, we show that GBM cells carrying EGFR EC mutations display EGFR addiction. In contrast to KD mutants found in lung cancer, glioma-specific EGFR EC mutants are poorly inhibited by EGFR inhibitors that target the active kinase conformation (e.g., erlotinib). Inhibitors that bind to the inactive EGFR conformation, however, potently inhibit EGFR EC mutants and induce cell death in EGFR-mutant GBM cells. Our results provide first evidence for single kinase addiction in GBM and suggest that the disappointing clinical activity of first-generation EGFR inhibitors in GBM versus lung cancer may be attributed to the different conformational requirements of mutant EGFR in these 2 cancer types. SIGNIFICANCE: Approximately 40% of human glioblastomas harbor oncogenic EGFR alterations, but attempts to therapeutically target EGFR with first-generation EGFR kinase inhibitors have failed. Here, we demonstrate selective sensitivity of glioma-specific EGFR mutants to ATP-site competitive EGFR kinase inhibitors that target the inactive conformation of the catalytic domain.

1 Bookmark
  • [Show abstract] [Hide abstract]
    ABSTRACT: Diffuse intrinsic pontine glioma (DIPG) is a disease of childhood whose abysmal prognosis has remained unchanged for over 50 years. Biologic investigation has been stymied by lack of pretreatment tissue, as biopsy has been reserved for atypical cases. Recent advances in surgical and molecular-analytic techniques have increased the safety and potential utility of biopsy; brainstem biopsy has now been incorporated into several prospective clinical trials. These and other recent efforts have yielded new insights into DIPG molecular pathogenesis, and opened new avenues for investigation.
    Journal of Neuro-Oncology 05/2014; · 3.12 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Medical treatments for glioblastoma face several challenges. Lipophilic alkylators remain the mainstay of treatment, emphasising the primacy of good blood-brain barrier penetration. Temozolomide has emerged as a major contributor to improved patient survival. The roles of procarbazine and vincristine in the procarbazine, lomustine and vincristine (PCV) schedule have attracted scrutiny and several lines of evidence now support the use of lomustine as effective single-agent therapy. Bevacizumab has had a convoluted development history, but clearly now has no major role in first-line treatment, and may even be detrimental to quality of life in this setting. In later disease, clinically meaningful benefits are achievable in some patients, but more impressively the combination of bevacizumab and lomustine shows early promise. Over the last decade, investigational strategies in glioblastoma have largely subscribed to the targeted kinase inhibitor paradigm and have mostly failed. Low prevalence dominant driver lesions such as the FGFR-TACC fusion may represent a niche role for this agent class. Immunological, metabolic and radiosensitising approaches are being pursued and offer more generalised efficacy. Finally, trial design is a crucial consideration. Progress in clinical glioblastoma research would be greatly facilitated by improved methodologies incorporating: (i) routine pharmacokinetic and pharmacodynamic assessments by preoperative dosing; and (ii) multi-stage, multi-arm protocols incorporating new therapy approaches and high-resolution biology in order to guide necessary improvements in science.
    Clinical Oncology 04/2014; · 2.86 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Glioblastoma is a particularly resilient cancer, and while therapies may be able to reach the brain by crossing the blood-brain barrier, they then have to deal with a highly invasive tumor that is very resistant to DNA damage. It seems clear that in order to kill aggressive glioma cells more efficiently and with fewer side effects on normal tissue, there must be a shift from classical cytotoxic chemotherapy to more targeted therapies. Since the epidermal growth factor receptor (EGFR) is altered in almost 50 % of glioblastomas, it currently represents one of the most promising therapeutic targets. In fact, it has been associated with several distinct steps in tumorigenesis, from tumor initiation to tumor growth and survival, and also with the regulation of cell migration and angiogenesis. However, inhibitors of the EGFR kinase have produced poor results with this type of cancer in clinical trials, with no clear explanation for the tumor resistance observed. Here we will review what we know about the expression and function of EGFR in cancer and in particular in gliomas. We will also evaluate which are the possible molecular and cellular escape mechanisms. As a result, we hope that this review will help improve the design of future EGFR-targeted therapies for glioblastomas.
    Cellular and Molecular Life Sciences CMLS 03/2014; · 5.62 Impact Factor

Full-text (2 Sources)

Available from
May 19, 2014