Abstract
Targeted therapy against epidermal growth factor receptor (EGFR) represents a major therapeutic advance in lung cancer treatment. Somatic mutations of the EGFR gene, most commonly L858R (exon 21) and short in-frame exon 19 deletions, have been found to confer enhanced sensitivity toward the inhibitors gefitinib and erlotinib. We have recently identified an EGFR mutation E884K, in combination with L858R, in a patient with advanced lung cancer who progressed on erlotinib maintenance therapy, and subsequently had leptomeningeal metastases that responded to gefitinib. The somatic E884K substitution appears to be relatively infrequent and resulted in a mutant lysine residue that disrupts an ion pair with residue R958 in the EGFR kinase domain C-lobe, an interaction that is highly conserved within the human kinome as demonstrated by our sequence analysis and structure analysis. Our studies here, using COS-7 transfection model system, show that E884K works in concert with L858R in-cis, in a dominant manner, to change downstream signaling, differentially induce Mitogen-activated protein kinase (extracellular signaling-regulated kinase 1/2) signaling and associated cell proliferation and differentially alter sensitivity of EGFR phosphorylation inhibition by ERBB family inhibitors in an inhibitor-specific manner. Mutations of the conserved ion pair E884–R958 may result in conformational changes that alter kinase substrate recognition. The analogous E1271K-MET mutation conferred differential sensitivity toward preclinical MET inhibitors SU11274 (unchanged) and PHA665752 (more sensitive). Systematic bioinformatics analysis of the mutation catalog in the human kinome revealed the presence of cancer-associated mutations involving the conserved E884 homologous residue, and adjacent residues at the ion pair, in known proto-oncogenes (KIT, RET, MET and FAK) and tumor-suppressor gene (LKB1). Targeted therapy using small-molecule inhibitors should take into account potential cooperative effects of multiple kinase mutations, and their specific effects on downstream signaling and inhibitor sensitivity. Improved efficacy of targeted kinase inhibitors may be achieved by targeting the dominant activating mutations present.
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Abbreviations
- COSMIC:
-
catalogue of somatic mutations in cancer
- EGFR:
-
epidermal growth factor receptor
- MAPK (ERK1/2):
-
mitogen-activated protein kinase (extracellular signaling-regulated kinase 1/2)
- STAT3:
-
signal transducer and activator of transcription 3
- TKI:
-
tyrosine kinase inhibitor
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Acknowledgements
Patrick C Ma is supported by NIH/National Cancer Institute-K08 Career Development Award (5K08CA102545-04), American Cancer Society (Ohio)-Institutional Research Grant (IRG-91-022, Case Comprehensive Cancer Center) and Ohio Cancer Research Associates (Give New Ideas A Chance) Grant Award. Titus J Boggon is an American Society of Hematology Junior Faculty Scholar. Edward T Petri is supported by an NIH/National Cancer Institute T32 training Grant (5T32CA009085-32). We thank Dr Zhenghe J Wang (Department of Genetics, Case Western Reserve University) for critically reading the manuscript and for helpful suggestions.
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Tang, Z., Jiang, S., Du, R. et al. Disruption of the EGFR E884–R958 ion pair conserved in the human kinome differentially alters signaling and inhibitor sensitivity. Oncogene 28, 518–533 (2009). https://doi.org/10.1038/onc.2008.411
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DOI: https://doi.org/10.1038/onc.2008.411
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