Abstract
BackgroundMutations 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 FindingsUsing 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.ConclusionsIn 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.
Highlights
Lung adenocarcinomas that harbor somatic kinase domain mutations in the epidermal growth factor receptor (EGFR) are highly likely to respond to the EGFR tyrosine kinase inhibitors gefitinib (Iressa) and erlotinib (Tarceva) [1,2,3]
In drug-sensitive EGFR mutant lung cancer cells, induction of BIM is essential for apoptosis triggered by EGFR kinase inhibitors
To determine which BCL2 family members are potentially involved in the maintenance of tumors by mutant EGFR, we studied the effect of erlotinib treatment on the expression of BCL2, BCLxL, myeloid cell leukemia sequence 1 (MCL1), BCL2associated X protein (BAX), BCL2 antagonist/killer (BAK), BIM, BAD, and PUMA in H3255 cells
Summary
Lung adenocarcinomas that harbor somatic kinase domain mutations in the epidermal growth factor receptor (EGFR) are highly likely to respond to the EGFR tyrosine kinase inhibitors gefitinib (Iressa) and erlotinib (Tarceva) [1,2,3]. Drug responses have been characterized in limited detail in a few drug-sensitive human lung adenocarcinoma cell lines that harbor EGFR mutations These studies indicate that EGFR kinase inhibitors can induce the activation of cysteine aspartyl-specific proteases (caspases) in EGFR mutant cells [4,5,6,7]. Mutations in the epidermal growth factor receptor (EGFR) gene are associated with increased sensitivity of lung cancers to kinase inhibitors like erlotinib. ‘‘targeted’’ therapies have brought new hope to some patients with cancer These therapies attack the changes in cancer cells that allow them to divide uncontrollably but leave normal cells unscathed. Messenger proteins bind to EGFR and activate its ‘‘tyrosine kinase,’’ an enzyme that sticks phosphate groups on tyrosine (an amino acid) in other proteins These proteins tell the cell to divide. Some lung cancers with mutations in the tyrosine kinase of EGFR shrink dramatically when treated with gefitinib or erlotinib, two tyrosine kinase inhibitors (TKIs)
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