Identification of substrates of lung cancer-specific mutant EGFR kinases

Monday, October 24, 2011 — Poster Session I
Noon – 2:00 p.m.	Natcher Conference Center	NCI	CANCER-14

Authors

• T Maity
• HS Rho
• H Zhu
• U Guha

Abstract

Somatic mutations in the kinase domain of epidermal growth factor receptor (EGFR) that occur in a subset of patients with lung adenocarcinoma are associated with sensitivity to tyrosine kinase inhibitors (TKIs). However, all patients who respond initially to TKIs eventually develop secondary resistance. The most common cause of this secondary resistance is a mutation in the gatekeeper residue in the ATP binding pocket of EGFR (T790M) that occurs in 50% of cases. We hypothesized that mutant EGFR kinases have altered substrate specificity. We have used an in-vitro kinase assay on protein array chips containing around 17,000 proteins to compare the substrate specificity of the kinase domains of wild type EGFR, L858R EGFR (the most common activating mutant), and the EGFR harboring both the L858R and T790M mutations (TKI resistant mutant). We are validating potential substrates of mutant EGFRs identified from this screen in human lung adenocarcinoma cells, mouse models of lung tumorigenesis induced by mutant EGFRs, and patient samples of lung adenocarcinoma. We have used shRNA gene silencing to elucidate the role of several of these substrates in survival of lung adenocarcinoma cells. Our approach has the potential to identify new generation drug-targets in lung adenocarcinoma.

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