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Article: Identification and characterization of ALK kinase splicing isoforms in non-small-cell lung cancer

TitleIdentification and characterization of ALK kinase splicing isoforms in non-small-cell lung cancer
Authors
Issue Date2014
PublisherLippincott Williams & Wilkins.
Citation
Journal of Thoracic Oncology, 2014, v. 9 n. 2, p. 248–253 How to Cite?
AbstractINTRODUCTION: Anaplastic lymphoma kinase (ALK) rearrangements are present in an important subset of non-small-cell lung cancer (NSCLC) and predict for response to the tyrosine kinase inhibitor crizotinib. In this study, we evaluated the yet unknown frequency and functional role of ALK splicing isoforms in NSCLC. METHODS: We analyzed 270 cases of NSCLC for ALK kinase domain splicing aberrations and in addition generated constructs with full-length echinoderm microtubule-associated protein-like 4 (EML4)-ALK (E13;A20) and a splicing isoform. RESULTS: Splicing isoforms of the kinase domain of ALK-including complete skipping of exon 23 (ALKdel23, ALK p.I1171fs*42) and exon 27 (ALKdel27, ALK p.T1312fs*0)-were identified in 11.1% (30 of 270 cases) of NSCLC, and these changes coexisted with ALK rearrangements, KRAS mutations, and EGFR mutations. ALK splicing isoforms were observed with full-length EML4-ALK in crizotinib-naive and treated NSCLCs. ALK T1312fs*0 was unable to render cells solely dependent on ALK signaling. Unlike EML4-ALK and EML4-ALK p.L1196M, EML4-ALK T1312fs*0 did not autophosphorylate ALK or other phosphotyrosine sites. Coexpression of equal amounts of EML4-ALK T1312fs*0 and EML4-ALK did not result in resistance to crizotinib, whereas coexpression of EML4-ALK L1196M with EML4-ALK resulted in resistance to inhibition of ALK by crizotinib. CONCLUSIONS: ALK kinase splicing isoforms were present in NSCLC and even if translated seemed to be nonfunctional variants of ALK.
Persistent Identifierhttp://hdl.handle.net/10722/194992
ISSN
2015 Impact Factor: 5.04
2015 SCImago Journal Rankings: 2.597
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorde Figueiredo-Pontes, LLen_US
dc.contributor.authorWong, DWSen_US
dc.contributor.authorTin, PCen_US
dc.contributor.authorChung, LPen_US
dc.contributor.authorYasuda, Hen_US
dc.contributor.authorYamaguchi, Nen_US
dc.contributor.authorNakayama, Sen_US
dc.contributor.authorJänne, PAen_US
dc.contributor.authorWong, MPen_US
dc.contributor.authorKobayashi, SSen_US
dc.contributor.authorCosta, DBen_US
dc.date.accessioned2014-02-21T06:44:37Z-
dc.date.available2014-02-21T06:44:37Z-
dc.date.issued2014en_US
dc.identifier.citationJournal of Thoracic Oncology, 2014, v. 9 n. 2, p. 248–253en_US
dc.identifier.issn1556-0864-
dc.identifier.urihttp://hdl.handle.net/10722/194992-
dc.description.abstractINTRODUCTION: Anaplastic lymphoma kinase (ALK) rearrangements are present in an important subset of non-small-cell lung cancer (NSCLC) and predict for response to the tyrosine kinase inhibitor crizotinib. In this study, we evaluated the yet unknown frequency and functional role of ALK splicing isoforms in NSCLC. METHODS: We analyzed 270 cases of NSCLC for ALK kinase domain splicing aberrations and in addition generated constructs with full-length echinoderm microtubule-associated protein-like 4 (EML4)-ALK (E13;A20) and a splicing isoform. RESULTS: Splicing isoforms of the kinase domain of ALK-including complete skipping of exon 23 (ALKdel23, ALK p.I1171fs*42) and exon 27 (ALKdel27, ALK p.T1312fs*0)-were identified in 11.1% (30 of 270 cases) of NSCLC, and these changes coexisted with ALK rearrangements, KRAS mutations, and EGFR mutations. ALK splicing isoforms were observed with full-length EML4-ALK in crizotinib-naive and treated NSCLCs. ALK T1312fs*0 was unable to render cells solely dependent on ALK signaling. Unlike EML4-ALK and EML4-ALK p.L1196M, EML4-ALK T1312fs*0 did not autophosphorylate ALK or other phosphotyrosine sites. Coexpression of equal amounts of EML4-ALK T1312fs*0 and EML4-ALK did not result in resistance to crizotinib, whereas coexpression of EML4-ALK L1196M with EML4-ALK resulted in resistance to inhibition of ALK by crizotinib. CONCLUSIONS: ALK kinase splicing isoforms were present in NSCLC and even if translated seemed to be nonfunctional variants of ALK.en_US
dc.languageengen_US
dc.publisherLippincott Williams & Wilkins.-
dc.relation.ispartofJournal of Thoracic Oncologyen_US
dc.titleIdentification and characterization of ALK kinase splicing isoforms in non-small-cell lung canceren_US
dc.typeArticleen_US
dc.identifier.emailTin, PC: pctin@hku.hken_US
dc.identifier.emailChung, LP: lpchung@hkucc.hku.hken_US
dc.identifier.emailWong, MP: mwpik@hku.hken_US
dc.identifier.authorityChung, LP=rp00249en_US
dc.identifier.authorityWong, MP=rp00348en_US
dc.identifier.doi10.1097/JTO.0000000000000050en_US
dc.identifier.pmid24419423-
dc.identifier.hkuros228071en_US
dc.identifier.volume9en_US
dc.identifier.issue2en_US
dc.identifier.spage248–253en_US
dc.identifier.epage248–253en_US
dc.identifier.isiWOS:000330078100023-
dc.publisher.placeUnited States-

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