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Article: Src promotes survival and invasion of lung cancers with epidermal growth factor receptor abnormalities and is a potential candidate for molecular-targeted therapy

TitleSrc promotes survival and invasion of lung cancers with epidermal growth factor receptor abnormalities and is a potential candidate for molecular-targeted therapy
Authors
Issue Date2009
PublisherAmerican Association for Cancer Research. The Journal's web site is located at http://mcr.aacrjournals.org/
Citation
Molecular Cancer Research, 2009, v. 7 n. 6, p. 923-932 How to Cite?
AbstractMolecular-targeted therapy using tyrosine kinase inhibitors against epidermal growth factor receptor (EGFR) is an effective therapy for non-small cell lung cancer that harbor EGFR mutations. This study aimed to investigate the role of Src, a close EGFR associator, as a drug target in NSCLC cells with different EGFR genomic statuses. Src inhibition was achieved using 4-(4′-Phenoxyanilino)-6,7-dimethoxyquinazolinee (SKI-1) and the specificity of action was verified by RNA interference. The results showed that SKI-1 induced significant apoptosis in a dose-dependent manner in cancer cells with high basal Src activation. Activation of FAK and p130Cas was involved in Src-mediated invasion in SKI-1-sensitive cells. SKI-1 inhibited phosphorylation of EGFR as well as EGFR downstream effectors, such as signal transducers and activators of transcription 3/5, extracellular signal-regulated kinase 1/2 and AKT in the mutant cells but not the wild-type cells. This inhibition profile of EGFR implicates that induction of apoptosis and sensitivity of mutant cells to SKI treatment is mediated by EGFR and EGFR downstream pathways. Cotreatment with SKI-1 and gefitinib enhanced apoptosis in cancer cells that contained EGFR mutation and/or amplification. SKI-1 treatment alone induced significant apoptosis in H1975 cells known to be resistant to gefitinib. Src phosphorylation was shown by immunohistochemistry in around 30% of primary lung carcinomas. In 152 adenocarcinomas studied, p-Src was associated with EGFR mutations (P = 0.029). Overall, the findings indicated that Src could be a useful target for treatment of non-small cell lung cancer. Besides EGFR genomic mutations, other forms of EGFR and related family member abnormalities such as EGFR amplification might enhance SKI sensitivity. Copyright © 2009 American Association for Cancer Research.
Persistent Identifierhttp://hdl.handle.net/10722/58605
ISSN
2015 Impact Factor: 4.51
2015 SCImago Journal Rankings: 2.534
ISI Accession Number ID
Funding AgencyGrant Number
CRGC10206721
University of Hong Kong200707176118
Funding Information:

CRGC 10206721 and small project Funding 200707176118 awarded by University of Hong Kong.

References

 

DC FieldValueLanguage
dc.contributor.authorLeung, ELHen_HK
dc.contributor.authorTam, IYSen_HK
dc.contributor.authorTin, VPCen_HK
dc.contributor.authorChua, DTTen_HK
dc.contributor.authorSihoe, ADLen_HK
dc.contributor.authorCheng, LCen_HK
dc.contributor.authorHo, JCMen_HK
dc.contributor.authorChung, LPen_HK
dc.contributor.authorWong, MPen_HK
dc.date.accessioned2010-05-31T03:33:22Z-
dc.date.available2010-05-31T03:33:22Z-
dc.date.issued2009en_HK
dc.identifier.citationMolecular Cancer Research, 2009, v. 7 n. 6, p. 923-932en_HK
dc.identifier.issn1541-7786en_HK
dc.identifier.urihttp://hdl.handle.net/10722/58605-
dc.description.abstractMolecular-targeted therapy using tyrosine kinase inhibitors against epidermal growth factor receptor (EGFR) is an effective therapy for non-small cell lung cancer that harbor EGFR mutations. This study aimed to investigate the role of Src, a close EGFR associator, as a drug target in NSCLC cells with different EGFR genomic statuses. Src inhibition was achieved using 4-(4′-Phenoxyanilino)-6,7-dimethoxyquinazolinee (SKI-1) and the specificity of action was verified by RNA interference. The results showed that SKI-1 induced significant apoptosis in a dose-dependent manner in cancer cells with high basal Src activation. Activation of FAK and p130Cas was involved in Src-mediated invasion in SKI-1-sensitive cells. SKI-1 inhibited phosphorylation of EGFR as well as EGFR downstream effectors, such as signal transducers and activators of transcription 3/5, extracellular signal-regulated kinase 1/2 and AKT in the mutant cells but not the wild-type cells. This inhibition profile of EGFR implicates that induction of apoptosis and sensitivity of mutant cells to SKI treatment is mediated by EGFR and EGFR downstream pathways. Cotreatment with SKI-1 and gefitinib enhanced apoptosis in cancer cells that contained EGFR mutation and/or amplification. SKI-1 treatment alone induced significant apoptosis in H1975 cells known to be resistant to gefitinib. Src phosphorylation was shown by immunohistochemistry in around 30% of primary lung carcinomas. In 152 adenocarcinomas studied, p-Src was associated with EGFR mutations (P = 0.029). Overall, the findings indicated that Src could be a useful target for treatment of non-small cell lung cancer. Besides EGFR genomic mutations, other forms of EGFR and related family member abnormalities such as EGFR amplification might enhance SKI sensitivity. Copyright © 2009 American Association for Cancer Research.en_HK
dc.languageengen_HK
dc.publisherAmerican Association for Cancer Research. The Journal's web site is located at http://mcr.aacrjournals.org/en_HK
dc.relation.ispartofMolecular Cancer Researchen_HK
dc.subject.meshApoptosis - drug effectsen_HK
dc.subject.meshCarcinoma, Non-Small-Cell Lung - enzymology - genetics - pathologyen_HK
dc.subject.meshCell Line, Tumoren_HK
dc.subject.meshCell Movement - drug effectsen_HK
dc.subject.meshGene Amplificationen_HK
dc.subject.meshHumansen_HK
dc.subject.meshImmunohistochemistryen_HK
dc.subject.meshLung Neoplasms - enzymology - genetics - pathologyen_HK
dc.subject.meshMutationen_HK
dc.subject.meshNeoplasm Invasivenessen_HK
dc.subject.meshPhosphorylation - drug effectsen_HK
dc.subject.meshProtein Kinase Inhibitors - pharmacologyen_HK
dc.subject.meshQuinazolines - pharmacologyen_HK
dc.subject.meshRNA, Small Interfering - genetics - metabolismen_HK
dc.subject.meshReceptor, Epidermal Growth Factor - antagonists & inhibitors - genetics - metabolismen_HK
dc.subject.meshReproducibility of Resultsen_HK
dc.subject.meshsrc-Family Kinases - antagonists & inhibitors - metabolismen_HK
dc.titleSrc promotes survival and invasion of lung cancers with epidermal growth factor receptor abnormalities and is a potential candidate for molecular-targeted therapyen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=1541-7786&volume=7&issue=6&spage=923&epage=32&date=2009&atitle=Src+Promotes+Survival+and+Invasion+of+Lung+Cancers+with+Epidermal+Growth+Factor+Receptor+Abnormalities+and+Is+a+Potential+Candidate+for+Molecular-Targeted+Therapy.en_HK
dc.identifier.emailChua, DTT: dttchua@hkucc.hku.hken_HK
dc.identifier.emailHo, JCM: jhocm@hku.hken_HK
dc.identifier.emailChung, LP: lpchung@hkucc.hku.hken_HK
dc.identifier.emailWong, MP: mwpik@hkucc.hku.hken_HK
dc.identifier.authorityChua, DTT=rp00415en_HK
dc.identifier.authorityHo, JCM=rp00258en_HK
dc.identifier.authorityChung, LP=rp00249en_HK
dc.identifier.authorityWong, MP=rp00348en_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1158/1541-7786.MCR-09-0003en_HK
dc.identifier.pmid19491201-
dc.identifier.scopuseid_2-s2.0-67649600824en_HK
dc.identifier.hkuros156043en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-67649600824&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume7en_HK
dc.identifier.issue6en_HK
dc.identifier.spage923en_HK
dc.identifier.epage932en_HK
dc.identifier.eissn1557-3125-
dc.identifier.isiWOS:000267312500016-
dc.publisher.placeUnited Statesen_HK
dc.identifier.scopusauthoridLeung, ELH=26531254500en_HK
dc.identifier.scopusauthoridTam, IYS=8244035800en_HK
dc.identifier.scopusauthoridTin, VPC=6603199735en_HK
dc.identifier.scopusauthoridChua, DTT=7006773480en_HK
dc.identifier.scopusauthoridSihoe, ADL=6603611976en_HK
dc.identifier.scopusauthoridCheng, LC=9533935800en_HK
dc.identifier.scopusauthoridHo, JCM=7402649981en_HK
dc.identifier.scopusauthoridChung, LP=24315879100en_HK
dc.identifier.scopusauthoridWong, MP=7403907887en_HK

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