Data from: Oncogenic transformation by inhibitor-sensitive and resistant EGFR mutants

Background   Somatic mutations in the kinase domain of the
epidermal growth factor receptor tyrosine kinase gene EGFR are common in
lung adenocarcinoma. The presence of mutations correlates with tumor
sensitivity to the EGFR inhibitors erlotinib and gefitinib, but the
transforming potential of specific mutations and their relationship to
drug sensitivity have not been described.   Methods and Findings
  Here, we demonstrate that EGFR active site mutants are
oncogenic. Mutant EGFR can transform both fibroblasts and lung epithelial
cells in the absence of exogenous epidermal growth factor, as evidenced by
anchorage-independent growth, focus formation, and tumor formation in
immunocompromised mice. Transformation is associated with constitutive
autophosphorylation of EGFR, Shc phosphorylation, and STAT pathway
activation. Whereas transformation by most EGFR mutants confers on cells
sensitivity to erlotinib and gefitinib, transformation by an exon 20
insertion makes cells resistant to these inhibitors but more sensitive to
the irreversible inhibitor CL-387,785.   Conclusion  
Oncogenic transformation of cells by different EGFR mutants causes
differential sensitivity to gefitinib and erlotinib. Treatment of lung
cancers harboring EGFR exon 20 insertions may therefore require the
development of alternative kinase inhibition strategies.