The role of cooperativity with Src in oncogenic transformation mediated by non-small cell lung cancer-associated EGF receptor mutants

• Published in: Oncogene Vol. 28; no. 16; pp. 1821 - 1832
• Main Authors: Chung, B M, Dimri, M, George, M, Reddi, A L, Chen, G, Band, V, Band, H
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 23.04.2009; Nature Publishing Group
• Subjects: AKT protein; Animals; Apoptosis; Biological and medical sciences; Carcinoma, Non-Small-Cell Lung - genetics; Cell Biology; Cell growth; Cell Movement; Cell physiology; Cell Proliferation; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cell Transformation, Neoplastic; Cooperativity; Drug therapy; Epidermal growth factor; Epidermal growth factor receptors; ErbB Receptors - genetics; Fundamental and applied biological sciences. Psychology; Gene mutations; Genetic aspects; Genetic transformation; Genetics; Health aspects; Human Genetics; Humans; Internal Medicine; Lung cancer; Lung cancer, Non-small cell; Lung Neoplasms - genetics; Medical sciences; Medicine; Medicine & Public Health; Mice; Molecular and cellular biology; Mutants; Mutation; NIH 3T3 Cells; Non-small cell lung carcinoma; Oncology; original-article; Phenylalanine; Phosphorylation; Pneumology; Signal Transduction; Small cell lung carcinoma; src-Family Kinases - physiology; Stat3 protein; Tumorigenesis; Tumors of the respiratory system and mediastinum; Tyrosine; United States; transformation; Src; mutant EGFR; Lung disease; Enzyme; Respiratory disease; Transferases; Malignant tumor; non-small cell lung carcinoma; Carcinogenesis; Epidermal growth factor receptor; Bronchus disease; Mutation; Protein-tyrosine kinase; Cancer
• DOI: 10.1038/onc.2009.31
• ISSN: 0950-9232

Non-small cell lung cancer (NSCLC)-associated epidermal growth factor receptor (EGFR) mutants are constitutively active and induce ligand-independent transformation in non-malignant cell lines. We investigated the possibility that the ability of mutant EGFRs to transform cells reflects a constitutive cooperativity with Src using a system in which the overexpression of mutant, but not wild-type, EGFR induced anchorage-independent cell growth. Src was constitutively activated and showed enhanced interaction with mutant EGFRs, suggesting that constitutive EGFR–Src cooperativity may contribute to mutant EGFR-mediated oncogenesis. Indeed, the mutant EGFR-mediated cell transformation was inhibited by Src- as well as EGFR-directed inhibitors. Importantly, a tyrosine to phenylalanine mutation of the major Src phosphorylation site on EGFR, Y845, reduced the constitutive phosphorylation of NSCLC-EGFR mutants, as well as that of STAT3, Akt, Erk and Src, and reduced the mutant EGFR–Src association as well as proliferation, migration and anchorage-independent growth. Reduced anchorage-independent growth and migration were also observed when dominant-negative-Src was expressed in mutant EGFR-expressing cells. Overall, our findings show that mutant EGFR–Src interaction and cooperativity play critical roles in constitutive engagement of the downstream signaling pathways that allow NSCLC-associated EGFR mutants to mediate oncogenesis, and support the rationale to target Src-dependent signaling pathways in mutant EGFR-mediated malignancies.