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Article: Double EGFR mutants containing rare EGFR mutant types show reduced in vitro response to gefitinib compared with common activating missense mutations

TitleDouble EGFR mutants containing rare EGFR mutant types show reduced in vitro response to gefitinib compared with common activating missense mutations
Authors
Issue Date2009
PublisherAmerican Association for Cancer Research. The Journal's web site is located at http://mct.aacrjournals.org/
Citation
Molecular Cancer Therapeutics, 2009, v. 8 n. 8, p. 2142-2151 How to Cite?
AbstractEpidermal growth factor receptor (EGFR) mutations are common in lung adenocarcinomas, especially from nonsmoking women of Asian descent. We have previously shown EGFR mutations occur in >70% of lung adenocarcinoma from nonsmokers in our population with a complex mutational profile, including 13% of EGFR double mutations. In this study, we investigated the in vitro gefitinib response of four EGFR double mutants identified in untreated patients, including Q787R+L858R, E709A+G719C, T790M+L858R, and H870R+L858R. The phosphorylation profiles of EGFR and downstream effectors AKT, STAT3/5, and ERK1/2 were compared by immunoblot analyses among the single and double mutants transfected into H358 cells. Results showed that mutants responded to in vitro gefitinib treatment with different sensitivities. The G719C and L858R single mutants showed the highest gefitinib sensitivity compared with the corresponding coexisting single mutants E709A, Q787R, H870R, and T790M. The double mutants E709A+G719C, Q787R+L858R, and H870R+L858R showed attenuated responses to gefitinib in the EGFR and downstream effector phosphorylation profiles compared with G719C or L858R alone. T790M+L858R showed strong resistance to gefitinib. Clinically, the patient whose tumor contained H870R+L858R showed tumor stabilization by 250 mg oral gefitinib daily but cerebral metastasis developed 6 months later. Correlation with the in vitro phosphorylation profile of H870R+L858R suggested that treatment failure was probably due to inadequate suppression of EGFR signaling by the drug level attainable in the cerebrospinal fluid at the given oral dosage. Overall, the findings suggested that rare types of EGFR substitution mutations could confer relative gefitinib resistance when combined with the common activating mutants. Copyright © 2009 American Association for Cancer Research.
Persistent Identifierhttp://hdl.handle.net/10722/148610
ISSN
2015 Impact Factor: 5.579
2015 SCImago Journal Rankings: 3.224
ISI Accession Number ID
Funding AgencyGrant Number
Research Grant Council, Hong Kong Special Administrative RegionHKU778708M
University of Hong Kong200707176118
Funding Information:

General Research Fund (HKU778708M) awarded by the Research Grant Council, Hong Kong Special Administrative Region, and the Small Project Fund (200707176118) awarded by The University of Hong Kong.

References

 

DC FieldValueLanguage
dc.contributor.authorTam, IYSen_HK
dc.contributor.authorLeung, ELHen_HK
dc.contributor.authorTin, VPCen_HK
dc.contributor.authorChua, DTTen_HK
dc.contributor.authorSihoe, ADLen_HK
dc.contributor.authorCheng, LCen_HK
dc.contributor.authorChung, LPen_HK
dc.contributor.authorWong, MPen_HK
dc.date.accessioned2012-05-29T06:14:06Z-
dc.date.available2012-05-29T06:14:06Z-
dc.date.issued2009en_HK
dc.identifier.citationMolecular Cancer Therapeutics, 2009, v. 8 n. 8, p. 2142-2151en_HK
dc.identifier.issn1535-7163en_HK
dc.identifier.urihttp://hdl.handle.net/10722/148610-
dc.description.abstractEpidermal growth factor receptor (EGFR) mutations are common in lung adenocarcinomas, especially from nonsmoking women of Asian descent. We have previously shown EGFR mutations occur in >70% of lung adenocarcinoma from nonsmokers in our population with a complex mutational profile, including 13% of EGFR double mutations. In this study, we investigated the in vitro gefitinib response of four EGFR double mutants identified in untreated patients, including Q787R+L858R, E709A+G719C, T790M+L858R, and H870R+L858R. The phosphorylation profiles of EGFR and downstream effectors AKT, STAT3/5, and ERK1/2 were compared by immunoblot analyses among the single and double mutants transfected into H358 cells. Results showed that mutants responded to in vitro gefitinib treatment with different sensitivities. The G719C and L858R single mutants showed the highest gefitinib sensitivity compared with the corresponding coexisting single mutants E709A, Q787R, H870R, and T790M. The double mutants E709A+G719C, Q787R+L858R, and H870R+L858R showed attenuated responses to gefitinib in the EGFR and downstream effector phosphorylation profiles compared with G719C or L858R alone. T790M+L858R showed strong resistance to gefitinib. Clinically, the patient whose tumor contained H870R+L858R showed tumor stabilization by 250 mg oral gefitinib daily but cerebral metastasis developed 6 months later. Correlation with the in vitro phosphorylation profile of H870R+L858R suggested that treatment failure was probably due to inadequate suppression of EGFR signaling by the drug level attainable in the cerebrospinal fluid at the given oral dosage. Overall, the findings suggested that rare types of EGFR substitution mutations could confer relative gefitinib resistance when combined with the common activating mutants. Copyright © 2009 American Association for Cancer Research.en_HK
dc.languageengen_US
dc.publisherAmerican Association for Cancer Research. The Journal's web site is located at http://mct.aacrjournals.org/en_HK
dc.relation.ispartofMolecular Cancer Therapeuticsen_HK
dc.subject.meshAgeden_US
dc.subject.meshAntineoplastic Agents - Pharmacologyen_US
dc.subject.meshCarcinoma, Non-Small-Cell Lung - Drug Therapy - Geneticsen_US
dc.subject.meshCell Line, Tumoren_US
dc.subject.meshDrug Resistance, Neoplasmen_US
dc.subject.meshFemaleen_US
dc.subject.meshHumansen_US
dc.subject.meshLung Neoplasms - Drug Therapy - Geneticsen_US
dc.subject.meshMaleen_US
dc.subject.meshMiddle Ageden_US
dc.subject.meshMutation, Missenseen_US
dc.subject.meshPhosphorylationen_US
dc.subject.meshQuinazolines - Pharmacologyen_US
dc.subject.meshReceptor, Epidermal Growth Factor - Antagonists & Inhibitors - Genetics - Metabolismen_US
dc.subject.meshTyrosineen_US
dc.titleDouble EGFR mutants containing rare EGFR mutant types show reduced in vitro response to gefitinib compared with common activating missense mutationsen_HK
dc.typeArticleen_HK
dc.identifier.emailChua, DTT: dttchua@hkucc.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.authorityChung, LP=rp00249en_HK
dc.identifier.authorityWong, MP=rp00348en_HK
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1158/1535-7163.MCT-08-1219en_HK
dc.identifier.pmid19671738-
dc.identifier.scopuseid_2-s2.0-68849105058en_HK
dc.identifier.hkuros156044en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-68849105058&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume8en_HK
dc.identifier.issue8en_HK
dc.identifier.spage2142en_HK
dc.identifier.epage2151en_HK
dc.identifier.eissn1538-8514-
dc.identifier.isiWOS:000269029300009-
dc.publisher.placeUnited Statesen_HK
dc.identifier.scopusauthoridTam, IYS=8244035800en_HK
dc.identifier.scopusauthoridLeung, ELH=26531254500en_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.scopusauthoridChung, LP=24315879100en_HK
dc.identifier.scopusauthoridWong, MP=7403907887en_HK

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