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

BIM mediates EGFR tyrosine kinase inhibitor-induced apoptosis in lung cancers with oncogenic EGFR mutations. Research Abstract Details 

Research Abstract Table of Contents

Jump to the:

BIM mediates EGFR tyrosine kinase inhibitor-induced apoptosis in lung cancers with oncogenic EGFR mutations. Abstract Text:

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

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 EGFR-mutant 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.

BIM mediates EGFR tyrosine kinase inhibitor-induced apoptosis in lung cancers with oncogenic EGFR mutations. Publishing Authors By Initials

DB Costa,B Halmos,A Kumar,ST Schumer,MS Huberman,TJ Boggon,DG Tenen,S Kobayashi,DB Costa,B Halmos,A Kumar,ST Schumer,MS Huberman,TJ Boggon,DG Tenen,S Kobayashi,DB Costa,B Halmos,A Kumar,ST Schumer,MS Huberman,TJ Boggon,DG Tenen,S Kobayashi,

For similar abstracts research abstracts see: abstracts research

PUBMED ID PMID:

MEDLINE DATE:

BIM mediates EGFR tyrosine kinase inhibitor-induced apoptosis in lung cancers with oncogenic EGFR mutations. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: PLoS medicine

VOLUME: 4

Page Numbers: 1669-79; discussion 1680

Journal Abbreviation: PLoS Med.

ISSN: 1549-1676

DAY: 30

MONTH: Oct

YEAR: 2007

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

Number of References:

LANGUAGE: eng

NlmUniqueID: 101231360

BIM mediates EGFR tyrosine kinase inhibitor-induced apoptosis in lung cancers with oncogenic EGFR mutations. Keywords Mesh Terms:

KEYWORDS:

MESH TERMS:

Chemical & Substance for Abstract: BIM mediates EGFR tyrosine kinase inhibitor-induced apoptosis in lung cancers with oncogenic EGFR mutations. Information

Substance Name:

Registry Number:

Grant and Affiliation Information for BIM mediates EGFR tyrosine kinase inhibitor-induced apoptosis in lung cancers with oncogenic EGFR mutations.

AFFILIATION: Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.

Country: United States

AGENCY: United States NCI

GRANT: K99CA126026

ACRONYM: CA

MEDLINETA: PLoS Med

REFSOURCE:

DATABASENAME:

ACCESSION NUMBER:

Number Hits: 0

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

• A comparison of the emission efficiency of four common green fluorescence dyes after internalization into cancer cells.
• A novel mutation (Gln433Glu) in exon 12 combined with the G insertion in exon 13 causes severe factor XI deficiency in Japanese patients.
• A vicious cycle in the oral health status of schoolchildren in a primary school in rural Cambodia.
• Alkaliphilic Bacillus sp. strain KSM-LD1 contains a record number of subtilisin-like serine proteases genes.
• Amygdala-dependent Mechanisms Underlying Memory Retrieval of Conditioned Taste Aversion.
• Bone regeneration through controlled release of bone morphogenetic protein-2 from 3-D tissue engineered nano-scaffold.
• Cadaveric Hands-on Workshop Using a Three-Dimensional High-Definition Television System.
• Comparison of the antivascular and cytotoxic activities of TZT-1027 (Soblidotin) with those of other anticancer agents.
• Differentiation of mouse embryonic stem cells to hepatocyte-like cells by co-culture with human liver nonparenchymal cell lines.
• Heart Rate and Muscle Oxygenation during Hyperbaric Hyperoxia: 2343: Board #22 June 1 3:30 PM -5:00 PM.
• Hepatic uptake of bilirubin re-visited.
• MAMO, a maternal BTB/POZ-Zn-finger protein enriched in germline progenitors is required for the production of functional eggs in Drosophila.
• Maintenance behaviour and long-lasting insecticide-treated nets (LLITNs) previously introduced into Bourapar district, Khammouane province, Lao PDR.
• Management of the patients with early stage oral tongue cancers.
• Noise can delay and advance the collapse of spatiotemporal chaos.
• Phosphine oxides as efficient neutral coordinate-organocatalysts for stereoselective allylation of N-acylhydrazones.
• Porous imprinted polymer membranes prepared by phase separation in compressed liquid CO(2).
• Protective effect of alpha-tocopherol-6-O-phosphate against ultraviolet B-induced damage in cultured mouse skin.
• Pyothorax-associated lymphoma: A case showing transition from T-cell-rich polymorphic lesion to diffuse large B-cell lymphoma.
• Response of matrix metalloproteinase-9 to olfactory nerve injury.
• Single-pass BPM system of the Photon Factory storage ring.
• Spectral near-infrared fluorescence imaging of curved surfaces using projection reconstruction algorithms.
• Staphylococcus aureus cell-envelope antigens are localized in glomeruli from patients with IgA-related nephropathy.
• Steplike lattice deformation of single crystalline (La0.4Pr0.6)1.2Sr1.8Mn2O7 bilayered manganite.
• The Hes gene family: repressors and oscillators that orchestrate embryogenesis.
• The Odor Stick Identification Test for the Japanese (OSIT-J): Clinical Suitability for Patients Suffering from Olfactory Disturbance.
• Topical Application of gamma-Tocopherol Derivative Prevents UV-Induced Skin Pigmentation.
• Topical application of a novel, hydrophilic gamma-tocopherol derivative reduces photo-inflammation in mice skin.
• Which is the better pathological prognostic factor, the Nottingham histological grade or the Japanese nuclear grade? A large scale study with a long-term follow-up.
• Zinc finger protein STOP1 is critical for proton tolerance in Arabidopsis and coregulates a key gene in aluminum tolerance.