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A Combined 3D Tissue Engineered In Vitro/In Silico Lung Tumor Model for Predicting Drug Effectiveness in Specific Mutational Backgrounds
13:34

A Combined 3D Tissue Engineered In Vitro/In Silico Lung Tumor Model for Predicting Drug Effectiveness in Specific Mutational Backgrounds

Published on: April 6, 2016

Epidermal growth factor receptor variant III mutations in lung tumorigenesis and sensitivity to tyrosine kinase

Hongbin Ji1, Xiaojun Zhao, Yuki Yuza

  • 1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.

Proceedings of the National Academy of Sciences of the United States of America
|May 5, 2006
PubMed

Insights

Epidermal growth factor receptor variant III (EGFRvIII) drives non-small cell lung cancer (NSCLC) development and maintenance. An irreversible EGFR inhibitor effectively treated EGFRvIII-driven lung tumors, suggesting a new therapeutic strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Tyrosine kinase inhibitors like gefitinib and erlotinib show efficacy in non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations.
  • These inhibitors have limited efficacy in glioblastoma, which often harbors the distinct EGFR variant III (EGFRvIII) mutation.
  • The role and therapeutic targeting of EGFRvIII in lung cancer remain incompletely understood.

Purpose of the Study:

  • To investigate the presence and role of the EGFRvIII mutation in lung tumorigenesis.
  • To evaluate the response of EGFRvIII-driven lung tumors to tyrosine kinase inhibition.

Main Methods:

  • Analysis of EGFRvIII mutation status in human lung squamous cell carcinoma and adenocarcinoma.
  • Induction of EGFRvIII expression in murine lung tissue to model NSCLC.
  • Assessment of tumor growth and response to EGFR inhibitors (gefitinib, erlotinib, HKI-272) in vitro and in vivo.

Main Results:

  • EGFRvIII mutation was found in 5% of lung squamous cell carcinomas but not in lung adenocarcinomas.
  • Tissue-specific expression of EGFRvIII in mouse lungs induced NSCLC, which depended on EGFRvIII for maintenance.
  • EGFRvIII-driven murine lung tumors showed dramatic regression upon treatment with the irreversible EGFR inhibitor HKI-272.
  • EGFRvIII-mutated Ba/F3 cells were resistant to gefitinib/erlotinib but sensitive to HKI-272.

Conclusions:

  • EGFRvIII plays a critical role in the development and maintenance of a subset of lung cancers.
  • Irreversible EGFR inhibitors like HKI-272 represent a promising therapeutic strategy for cancers harboring the EGFRvIII mutation.

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