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Aberrant epidermal growth factor receptor signaling and enhanced sensitivity to EGFR inhibitors in lung cancer
Joseph Amann1, Shailaja Kalyankrishna, Pierre P Massion
1Vanderbilt-Ingram Cancer Center, Nashville, TN 37232, USA.
Abstract:
Epidermal growth factor receptor (EGFR) is occasionally amplified and/or mutated in non-small cell lung cancer (NSCLC) and can be coexpressed with other members of the HER receptor family to form functional heterodimers. We therefore investigated lung cancer cell lines for alterations in EGFR gene copy number, enhanced expression of EGFR and other HER family members, and EGFR coding sequence mutations and correlated these findings with response to treatment with the EGFR inhibitors and the kinetics of ligand-induced signaling. We show here that somatic deletions in the tyrosine kinase domain of EGFR were associated with increased EGFR gene copy number in NSCLC. Treatment with the specific EGFR tyrosine kinase inhibitors (TKI) gefitinib or erlotinib or the EGFR inhibitory antibody cetuximab induced apoptosis of HCC827, a NSCLC cell line with EGFR gene amplification and an exon 19 deletion. H1819, a NSCLC cell line that expresses high levels of EGFR, ErbB2, and ErbB3 but has wild-type EGFR, showed intermediate sensitivity to TKIs. In both cell lines, ligand-induced receptor tyrosine phosphorylation was delayed and prolonged and AKT was constitutively phosphorylated (but remained inhibitable by EGFR TKI). Thus, in addition to EGFR mutations, other factors in NSCLC cells, such as high expression of ErbB family members, may constitutively activate AKT and sensitize cells to EGFR inhibitors.
Insights
Epidermal growth factor receptor (EGFR) alterations in non-small cell lung cancer (NSCLC) influence treatment response. High expression of HER family members, alongside EGFR mutations, can sensitize NSCLC cells to EGFR inhibitors.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Epidermal growth factor receptor (EGFR) is implicated in non-small cell lung cancer (NSCLC) development.
- EGFR alterations, including amplification and mutations, are observed in NSCLC.
- EGFR can form heterodimers with other HER family members, impacting signaling pathways.
Purpose of the Study:
- To investigate EGFR gene copy number alterations, expression of EGFR and HER family members, and EGFR mutations in NSCLC cell lines.
- To correlate these genetic findings with cellular response to EGFR inhibitors.
- To analyze the kinetics of ligand-induced signaling in response to EGFR inhibition.
Main Methods:
- Analysis of EGFR gene copy number and coding sequence mutations in NSCLC cell lines.
- Assessment of EGFR and other HER family member expression levels.
- Treatment of NSCLC cell lines with EGFR tyrosine kinase inhibitors (TKIs) and an EGFR inhibitory antibody.
- Measurement of ligand-induced receptor tyrosine phosphorylation and AKT phosphorylation.
Main Results:
- Somatic deletions in the EGFR tyrosine kinase domain correlated with increased EGFR gene copy number in NSCLC.
- NSCLC cell lines with EGFR gene amplification and an exon 19 deletion (HCC827) showed apoptosis upon treatment with gefitinib, erlotinib, or cetuximab.
- A cell line with wild-type EGFR but high expression of EGFR, ErbB2, and ErbB3 (H1819) exhibited intermediate sensitivity to TKIs.
- Ligand-induced receptor tyrosine phosphorylation was delayed and prolonged in treated cell lines.
- AKT was constitutively phosphorylated in both cell lines, but remained inhibitable by EGFR TKI.
Conclusions:
- EGFR mutations are not the sole determinant of sensitivity to EGFR inhibitors in NSCLC.
- High expression of other ErbB family members can contribute to constitutive AKT activation.
- These factors may sensitize NSCLC cells to EGFR inhibitors, suggesting broader therapeutic targets.
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