Skip to main content

EGFRvIII and c-Met pathway inhibitors synergize against PTEN-null/EGFRvIII+ glioblastoma xenografts.

Publication ,  Journal Article
Lal, B; Goodwin, CR; Sang, Y; Foss, CA; Cornet, K; Muzamil, S; Pomper, MG; Kim, J; Laterra, J
Published in: Mol Cancer Ther
July 2009

Receptor tyrosine kinase (RTK) systems, such as hepatocyte growth factor (HGF) and its receptor c-Met, and epidermal growth factor receptor (EGFR), are responsible for the malignant progression of multiple solid tumors. Recent research shows that these RTK systems comodulate overlapping and dynamically adaptable oncogenic downstream signaling pathways. This study investigates how EGFRvIII, a constitutively active EGFR deletion mutant, alters tumor growth and signaling responses to RTK inhibition in PTEN-null/HGF(+)/c-Met(+) glioma xenografts. We show that a neutralizing anti-HGF monoclonal antibody (L2G7) potently inhibits tumor growth and the activation of Akt and mitogen-activated protein kinase (MAPK) in PTEN-null/HGF(+)/c-Met(+)/EGFRvIII(-) U87 glioma xenografts (U87wt). Isogenic EGFRvIII(+) U87 xenografts (U87-EGFRvIII), which grew five times more rapidly than U87-wt xenografts, were unresponsive to EGFRvIII inhibition by erlotinib and were only minimally responsive to anti-HGF monoclonal antibodies. EGFRvIII expression diminished the magnitude of Akt inhibition and completely prevented MAPK inhibition by L2G7. Despite the lack of response to L2G7 or erlotinib as single agents, their combination synergized to produce substantial antitumor effects (inhibited tumor cell proliferation, enhanced apoptosis, arrested tumor growth, prolonged animal survival), against subcutaneous and orthotopic U87-EGFRvIII xenografts. The dramatic response to combining HGF:c-Met and EGFRvIII pathway inhibitors in U87-EGFRvIII xenografts occurred in the absence of Akt and MAPK inhibition. These findings show that combining c-Met and EGFRvIII pathway inhibitors can generate potent antitumor effects in PTEN-null tumors. They also provide insights into how EGFRvIII and c-Met may alter signaling networks and reveal the potential limitations of certain biochemical biomarkers to predict the efficacy of RTK inhibition in genetically diverse cancers.

Duke Scholars

Altmetric Attention Stats
Dimensions Citation Stats

Published In

Mol Cancer Ther

DOI

EISSN

1538-8514

Publication Date

July 2009

Volume

8

Issue

7

Start / End Page

1751 / 1760

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Signal Transduction
  • Quinazolines
  • Proto-Oncogene Proteins c-met
  • Proto-Oncogene Proteins c-akt
  • Protein Kinase Inhibitors
  • PTEN Phosphohydrolase
  • Oncology & Carcinogenesis
  • Mitogen-Activated Protein Kinases
  • Mice, SCID
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Lal, B., Goodwin, C. R., Sang, Y., Foss, C. A., Cornet, K., Muzamil, S., … Laterra, J. (2009). EGFRvIII and c-Met pathway inhibitors synergize against PTEN-null/EGFRvIII+ glioblastoma xenografts. Mol Cancer Ther, 8(7), 1751–1760. https://doi.org/10.1158/1535-7163.MCT-09-0188
Lal, Bachchu, C Rory Goodwin, Yingying Sang, Catherine A. Foss, Kathrine Cornet, Sameena Muzamil, Martin G. Pomper, Jin Kim, and John Laterra. “EGFRvIII and c-Met pathway inhibitors synergize against PTEN-null/EGFRvIII+ glioblastoma xenografts.Mol Cancer Ther 8, no. 7 (July 2009): 1751–60. https://doi.org/10.1158/1535-7163.MCT-09-0188.
Lal B, Goodwin CR, Sang Y, Foss CA, Cornet K, Muzamil S, et al. EGFRvIII and c-Met pathway inhibitors synergize against PTEN-null/EGFRvIII+ glioblastoma xenografts. Mol Cancer Ther. 2009 Jul;8(7):1751–60.
Lal, Bachchu, et al. “EGFRvIII and c-Met pathway inhibitors synergize against PTEN-null/EGFRvIII+ glioblastoma xenografts.Mol Cancer Ther, vol. 8, no. 7, July 2009, pp. 1751–60. Pubmed, doi:10.1158/1535-7163.MCT-09-0188.
Lal B, Goodwin CR, Sang Y, Foss CA, Cornet K, Muzamil S, Pomper MG, Kim J, Laterra J. EGFRvIII and c-Met pathway inhibitors synergize against PTEN-null/EGFRvIII+ glioblastoma xenografts. Mol Cancer Ther. 2009 Jul;8(7):1751–1760.

Published In

Mol Cancer Ther

DOI

EISSN

1538-8514

Publication Date

July 2009

Volume

8

Issue

7

Start / End Page

1751 / 1760

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Signal Transduction
  • Quinazolines
  • Proto-Oncogene Proteins c-met
  • Proto-Oncogene Proteins c-akt
  • Protein Kinase Inhibitors
  • PTEN Phosphohydrolase
  • Oncology & Carcinogenesis
  • Mitogen-Activated Protein Kinases
  • Mice, SCID