Induction of BIM is essential for apoptosis triggered by EGFR kinase inhibitors in mutant EGFR-dependent lung adenocarcinomas Journal Article

Authors: Gong, Y.; Somwar, R.; Politi, K.; Balak, M.; Chmielecki, J.; Jiang, X.; Pao, W.
Article 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. Methods and Findings: 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 drugsensitive 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 erlotinibinduced 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. © 2007 Gong et al.
Keywords: mitogen activated protein kinase; controlled study; unclassified drug; gene mutation; human cell; erlotinib; nonhuman; mouse; protein bcl 2; apoptosis; enzyme inhibition; gene expression; animal experiment; animal model; bim protein; rna interference; genetic transcription; cancer cell culture; in vitro study; disease model; lung tumor; lung adenocarcinoma; drug mechanism; xenograft; gefitinib; protein induction; gene control; lung carcinoma; gene inactivation; cell killing; mutant; epidermal growth factor receptor kinase inhibitor; downstream processing; 4 [4 (4' chloro 2 biphenylylmethyl) 1 piperazinyl] n [4 [3 dimethylamino 1 (phenylthiomethyl)propylamino] 3 nitrobenzenesulfonyl]benzamide; bh3 protein; bcl 2 like 11 protein
Journal Title: PLos Medicine
Volume: 4
Issue: 10
ISSN: 1549-1277
Publisher: Public Library of Science  
Date Published: 2007-10-01
Start Page: 1655
End Page: 1668
Language: English
DOI: 10.1371/journal.pmed.0040294
PROVIDER: scopus
PMCID: PMC2001209
PUBMED: 17927446
Notes: --- - "Cited By (since 1996): 70" - "Export Date: 17 November 2011" - "Source: Scopus"
Altmetric Score
MSK Authors
  1. William Pao
    141 Pao
  2. Katerina A Politi
    23 Politi
  3. Romel Somwar
    37 Somwar
  4. Yixuan Gong
    15 Gong
  5. Xuejun Jiang
    82 Jiang
  6. Marissa Balak
    11 Balak