Date Published: October 9, 2007
Publisher: Public Library of Science
Author(s): Yixuan Gong, Romel Somwar, Katerina Politi, Marissa Balak, Juliann Chmielecki, Xuejun Jiang, William Pao, Ingo K Mellinghoff
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.
Partial Text: 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) [1–3]. One possible explanation for this phenomenon is that the cancer cells are “addicted” to signaling via the mutant EGFRs and die when the mutant oncoprotein is inactivated. However, specific mechanisms underlying erlotinib-induced cell death have not been well delineated.
Selective EGFR kinase inhibitors such as gefitinib and erlotinib induce tumor shrinkage in the majority of patients harboring mutant EGFR lung adenocarcinomas . Studies with cell lines and mouse lung tumor models suggest that such responses involve cell death, but the underlying mechanisms have not been well elucidated. Here, we sought to characterize pathways of apoptosis induced by this class of agents in mutant EGFR-dependent lung adenocarcinoma cells. An enhanced understanding of such processes could lead to the identification of even more effective therapeutic strategies. The studies were motivated by the fact that despite inducing dramatic clinical and radiographic tumor responses, gefitinib and erlotinib rarely induce complete responses and do not cure patients.