PDGFR[beta] Expression as a Mode of Resistance to EGFR Inhibition in Glioblastoma

Released on by David Akhavan
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  • PDGFR[beta] Expression as a Mode of Resistance to EGFR Inhibition in Glioblastoma Book Detail

  • Author : David Akhavan
  • Release Date : 2012
  • Publisher :
  • Genre :
  • Pages : 65
  • ISBN 13 :
  • File Size : 26,26 MB
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PDGFR[beta] Expression as a Mode of Resistance to EGFR Inhibition in Glioblastoma by David Akhavan PDF Summary

Book Description: Glioblastoma is the most common and most aggressive form of malignant primary brain tumor in adults. The epidermal growth factor receptor (EGFR) is a compelling molecular target in glioblastoma, because it is amplified, over-expressed, or mutated in nearly 50% of patients. Monotherapy clinical trials with EGFR inhibitors have shown benefit in only a subset of patients (10-15)% with limited duration of response. We have shown that glioblastoma patients whose tumors have a mutant form of the EGFR receptor, EGFRvIII, and have not lost the PTEN tumor suppressor protein are significantly more likely to respond to EGFR inhibitors and we have identified the molecular circuitry underlying this response1. This work, along with studies from others demonstrates that resistance to EGFR inhibitors may be mediated through maintenance of signal flux through the PI3K pathway2,3. Utilizing a variety of powerful resources - isogenic cell lines, low passage patient tumor cells, mouse models and clinical samples that include patients treated with EGFR inhibitors in clinical trials - my work is focused on identifying the molecular mechanisms of resistance to EGFR kinase inhibitors and on identifying targeted combination therapies to suppress it. We demonstrate that EGFR signaling potently suppresses PDGFR-beta transcription and protein expression in vitro and in vivo and that EGFR inhibition releases PDGFR-beta suppression in vitro and in vivo. We demonstrate clinical relevance by showing elevated PDGFR levels in GBM patients treated with EGFR/her2 kinase inhibitor lapatinib in a phase I clinical trial. Furthermore, we use a series of genetic and pharmacologic approaches to show that EGFR-dependent suppression of PDGFR-beta is mediated by mTORC1 signaling and demonstrate that PDGFR signaling maintains tumor growth in EGFR-inhibitor treated GBM models. These results provide a mechanistic basis by which GBMs switch from EGFR signaling to PDGFR-beta signaling in response to EGFR inhibitors and suggest that dual targeting of EGFR and PDGFR is required for more effective treatment. This work has the potential to explain a clinically important mechanism of resistance to EGFR inhibitor therapy and to develop more potent combination approaches for promoting long term disease suppression.

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