Oncogenic Transformation by Inhibitor-Sensitive and -Resistant EGFR Mutants

By H. Greulich, Tzu-Hsiu Chen, Whei Feng, P. Jänne, James V. Alvarez, M. Zappaterra, Sara E. Bulmer, D. Frank, William C. Hahn, William R. Sellers and 1 more. PLoS Medicine, 2005

677 citations recorded by the source corpus.

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.

Subfields: Molecular Biology, Oncology, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/afc07c6d295c1da5a84dbd5f726db04b8db9f8e2

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In Molecular Biology

1. Gwen Macdonald
2. J. Engelman
3. Matthew Meyerson
4. William Pao
5. M. Eck
6. G. Shapiro
7. D. Haber
8. N. Hynes

In Oncology

1. J. Engelman
2. P. Jänne
3. Gwen Macdonald
4. William Pao
5. G. Shapiro
6. N. Hynes
7. James E. Bradner
8. J. Chmielecki

In Pulmonary and Respiratory Medicine

1. J. Engelman
2. P. Jänne
3. William Pao
4. J. Chmielecki
5. N. Hynes
6. Gwen Macdonald
7. James E. Bradner
8. C. Sawyers

Citations in the corpus

• Mechanism for activation of the EGF receptor catalytic domain by the juxtamembrane segment (2009, neutral): “Notably, several insertions in exon 20 that drive constitutive EGFR activation are detected in lung cancer patients (Shigematsu et al., 2005; Greulich et al., 2005).”
• Rational, biologically based treatment of EGFR-mutant non-small-cell lung cancer (2010, background): “In vitro studies have shown that such mutations are less sensitive to EGFR TKIs than the exon 19 deletion and L858R mutant”
• AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. (2015, neutral): “Any grade 1 (5) 5 (9) 9 (10) 13 (21) 3 (14) 31 (12)”
• ErbB receptors and signaling pathways in cancer. (2009, background): “Considering lung cancer, the prosurvival PI3K/Akt and STAT pathways appear to be hyperactive in the context of mutant EGFRs [25,26].”
• BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models (2008, methodology): “, 2006); and EGF-stimulated wild-type EGFR (Greulich et al., 2005).”
• PF00299804, an irreversible pan-ERBB inhibitor, is effective in lung cancer models with EGFR and ERBB2 mutations that are resistant to gefitinib. (2007, methodology): “Furthermore, in vitro studies have shown that EGFR exon 20 mutations, which account for 1% to 3% of all EGFR mutations, are also resistant to the effects of gefitinib and erlotinib (22).”
• Epidermal growth factor receptor mutations in lung cancer (2007, background): “Consistent with their purported role in the aetiology of NSCLC, recent studies have shown that exon 19 deletions that involve the LREA motif, L858R, G719S and ins 770(NPG)-mutated EGFR proteins are oncogenic in both cell culture and transgenic mouse studie”
• Structures of lung cancer-derived EGFR mutants and inhibitor complexes: mechanism of activation and insights into differential inhibitor sensitivity. (2007, methodology): “…EGFR mutant tumors and cell lines may derive from an ‘‘oncogene addiction’’ effect (Gazdar et al., 2004), it may also stem, at least in part, from structural differences in the mutant kinases that confer intrinsic susceptibility to particular inhibitors (Lynch et al., 2004; Greulich et al., 2005).”