BIM mediates EGFR tyrosine kinase inhibitor-induced apoptosis in lung cancers with oncogenic EGFR mutations

Daniel B. Costa, Balazs Halmos, Amit Kumar, Susan T. Schumer, Mark S. Huberman, Titus J. Boggon, Daniel G. Tenen, Susumu Kobayashi

Research output: Contribution to journalArticle

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Abstract

Background: Epidermal growth factor receptor (EGFR) mutations are present in the majority of patients with non-small cell lung cancer (NSCLC) responsive to the EGFR tyrosine kinase inhibitors (TKIs) gefitinib or erlotinib. These EGFR-dependent tumors eventually become TKI resistant, and the common secondary T790M mutation accounts for half the tumors with acquired resistance to gefitinib. However, the key proapoptotic proteins involved in TKI-induced cell death and other secondary mutations involved in resistance remain unclear. The objective of this study was to identify the mechanism of EGFR TKI-induced apoptosis and secondary resistant mutations that affect this process. Methods and Findings: To study TKI-induced cell death and mechanisms of resistance, we used lung cancer cell lines (with or without EGFR mutations), Ba/F3 cells stably transfected with EGFR mutation constructs, and tumor samples from a gefitinib-resistant patient. Here we show that up-regulation of the BH3-only polypeptide BIM (also known as BCL2-like 11) correlated with gefitinib-induced apoptosis in gefitinib-sensitive EGFR-mutant lung cancer cells. The T790M mutation blocked gefitinib-induced up-regulation of BIM and apoptosis. This blockade was overcome by the irreversible TKI CL-387,785. Knockdown of BIM by small interfering RNA was able to attenuate apoptosis induced by EGFR TKIs. Furthermore, from a gefitinib-resistant patient carrying the activating L858R mutation, we identified a novel secondary resistant mutation, L747S in cis to the activating mutation, which attenuated the up-regulation of BIM and reduced apoptosis. Conclusions: Our results provide evidence that BIM is involved in TKI-induced apoptosis in sensitive EGFRmutant cells and that both attenuation of the up-regulation of BIM and resistance to gefitinib-induced apoptosis are seen in models that contain the common EGFR T790M and the novel L747S secondary resistance mutations. These findings also suggest that induction of BIM may have a role in the treatment of TKI-resistant tumors.

Original languageEnglish (US)
Pages (from-to)1669-1680
Number of pages12
JournalPLoS Medicine
Volume4
Issue number10
DOIs
StatePublished - Oct 2007
Externally publishedYes

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Epidermal Growth Factor Receptor
Protein-Tyrosine Kinases
Lung Neoplasms
Apoptosis
Mutation
Up-Regulation
Neoplasms
Cell Death
gefitinib
Non-Small Cell Lung Carcinoma
Small Interfering RNA
Cell Line
Peptides

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Costa, D. B., Halmos, B., Kumar, A., Schumer, S. T., Huberman, M. S., Boggon, T. J., ... Kobayashi, S. (2007). BIM mediates EGFR tyrosine kinase inhibitor-induced apoptosis in lung cancers with oncogenic EGFR mutations. PLoS Medicine, 4(10), 1669-1680. https://doi.org/10.1371/journal.pmed.0040315

BIM mediates EGFR tyrosine kinase inhibitor-induced apoptosis in lung cancers with oncogenic EGFR mutations. / Costa, Daniel B.; Halmos, Balazs; Kumar, Amit; Schumer, Susan T.; Huberman, Mark S.; Boggon, Titus J.; Tenen, Daniel G.; Kobayashi, Susumu.

In: PLoS Medicine, Vol. 4, No. 10, 10.2007, p. 1669-1680.

Research output: Contribution to journalArticle

Costa, DB, Halmos, B, Kumar, A, Schumer, ST, Huberman, MS, Boggon, TJ, Tenen, DG & Kobayashi, S 2007, 'BIM mediates EGFR tyrosine kinase inhibitor-induced apoptosis in lung cancers with oncogenic EGFR mutations', PLoS Medicine, vol. 4, no. 10, pp. 1669-1680. https://doi.org/10.1371/journal.pmed.0040315
Costa, Daniel B. ; Halmos, Balazs ; Kumar, Amit ; Schumer, Susan T. ; Huberman, Mark S. ; Boggon, Titus J. ; Tenen, Daniel G. ; Kobayashi, Susumu. / BIM mediates EGFR tyrosine kinase inhibitor-induced apoptosis in lung cancers with oncogenic EGFR mutations. In: PLoS Medicine. 2007 ; Vol. 4, No. 10. pp. 1669-1680.
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AU - Halmos, Balazs

AU - Kumar, Amit

AU - Schumer, Susan T.

AU - Huberman, Mark S.

AU - Boggon, Titus J.

AU - Tenen, Daniel G.

AU - Kobayashi, Susumu

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