title: Induction of BIM is essential for apoptosis triggered by EGFR kinase inhibitors in mutant EGFR-dependent lung adenocarcinomas.
abstract: BACKGROUND
  Mutations in the epidermal growth factor receptor (EGFR) gene are associated with increased sensitivity of lung cancers to kinase inhibitors like erlotinib. Mechanisms of cell death that occur after kinase inhibition in these oncogene-dependent tumors have not been well delineated. We sought to improve understanding of this process in order to provide insight into mechanisms of sensitivity and/or resistance to tyrosine kinase inhibitors and to uncover new targets for therapy.
  
  
  RESULTS
  Using a panel of human lung cancer cell lines that harbor EGFR mutations and a variety of biochemical, molecular, and cellular techniques, we show that EGFR kinase inhibition in drug-sensitive cells provokes apoptosis via the intrinsic pathway of caspase activation. The process requires induction of the proapoptotic BH3-only BCL2 family member BIM (i.e., BCL2-like 11, or BCL2L11); erlotinib dramatically induces BIM levels in sensitive but not in resistant cell lines, and knockdown of BIM expression by RNA interference virtually eliminates drug-induced cell killing in vitro. BIM status is regulated at both transcriptional and posttranscriptional levels and is influenced by the extracellular signal-regulated kinase (ERK) signaling cascade downstream of EGFR. Consistent with these findings, lung tumors and xenografts from mice bearing mutant EGFR-dependent lung adenocarcinomas display increased concentrations of Bim after erlotinib treatment. Moreover, an inhibitor of antiapoptotic proteins, ABT-737, enhances erlotinib-induced cell death in vitro.
  
  
  CONCLUSIONS
  In drug-sensitive EGFR mutant lung cancer cells, induction of BIM is essential for apoptosis triggered by EGFR kinase inhibitors. This finding implies that the intrinsic pathway of caspase activation may influence sensitivity and/or resistance of EGFR mutant lung tumor cells to EGFR kinase inhibition. Manipulation of the intrinsic pathway could be a therapeutic strategy to enhance further the clinical outcomes of patients with EGFR mutant lung tumors.
authors.affiliation: Pao Laboratory, Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Yixuan
authors.initials: Y
authors.lastname: Gong
authors.forename: Romel
authors.initials: R
authors.lastname: Somwar
authors.forename: Katerina
authors.initials: K
authors.lastname: Politi
authors.forename: Marissa
authors.initials: M
authors.lastname: Balak
authors.forename: Juliann
authors.initials: J
authors.lastname: Chmielecki
authors.forename: Xuejun
authors.initials: X
authors.lastname: Jiang
authors.forename: William
authors.initials: W
authors.lastname: Pao
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000235:genetics*; D000069347:Erlotinib Hydrochloride; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics; D051379:Mice; D009154:Mutation; D011799:Quinazolines / Q000494:pharmacology*; D012680:Sensitivity and Specificity; D051025:bcl-Associated Death Protein / Q000187:drug effects* / Q000235:genetics*
chemical_list: D011799:Quinazolines; D051025:bcl-Associated Death Protein; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors