Gefitinib-Sensitizing EGFR Mutations in Lung Cancer Activate Anti-Apoptotic Pathways

• DOI: 10.1126/science.1101637
• Publication Date: 2004-07-30T00:26:01Z
• Authors: Raffaella Sordella; Daphne W. Bell; Daniel A. Haber; Jeffrey Settleman
• Keywords: Lung Neoplasms; Cell Survival; Mutation, Missense; Antineoplastic Agents; Apoptosis; Gefitinib; Milk Proteins; Cell Line; 3. Good health; DNA-Binding Proteins; Enzyme Activation; ErbB Receptors; Mice; 03 medical and health sciences; 0302 clinical medicine; Carcinoma, Non-Small-Cell Lung; Catalytic Domain; Cell Line, Tumor; Mutation; Animals; Humans; Mitogen-Activated Protein Kinases; Phosphorylation

Gefitinib (Iressa, Astra Zeneca Pharmaceuticals) is a tyrosine kinase inhibitor that targets the epidermal growth factor receptor (EGFR) and induces dramatic clinical responses in nonsmall cell lung cancers (NSCLCs) with activating mutations within EGFR domain. We report these mutant EGFRs selectively activate Akt signal transduction activator of transcription (STAT) signaling pathways, which promote survival, but have no effect on extracellular signal–regulated signaling, proliferation. NSCLC cells expressing underwent extensive apoptosis after small interfering RNA–mediated knockdown or treatment pharmacological inhibitors STAT were relatively resistant to induced by conventional chemotherapeutic drugs. Thus, transduce survival signals NSCLCs become dependent; inhibition those gefitinib may contribute drug's efficacy.