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Article: C-Src activation mediates erlotinib resistance in head and neck cancer by stimulating c-Met

TitleC-Src activation mediates erlotinib resistance in head and neck cancer by stimulating c-Met
Authors
Issue Date2013
Citation
Clinical Cancer Research, 2013, v. 19 n. 2, p. 380-392 How to Cite?
AbstractPurpose: Strategies to inhibit the EGF receptor (EGFR) using the tyrosine kinase inhibitor erlotinib have been associated with limited clinical efficacy in head and neck squamous cell carcinoma (HNSCC). Co-activation of alternative kinases may contribute to erlotinib resistance. Experimental Design: We generated HNSCC cells expressing dominant-active c-Src (DA-Src) to determine the contribution of c-Src activation to erlotinib response. Results: Expression of DA-Src conferred resistance to erlotinib in vitro and in vivo compared with vectortransfected control cells. Phospho-Met was strongly upregulated by DA-Src, and DA-Src cells did not produce hepatocyte growth factor (HGF). Knockdown of c-Met enhanced sensitivity to erlotinib in DA-Src cells in vitro, as did combining a c-Met or c-Src inhibitor with erlotinib. Inhibiting EGFR resulted in minimal reduction of phospho-Met in DA-Src cells, whereas complete phospho-Met inhibition was achieved by inhibiting c-Src. A c-Met inhibitor significantly sensitized DA-Src tumors to erlotinib in vivo, resulting in reduced Ki67 labeling and increased apoptosis. In parental cells, knockdown of endogenous c-Src enhanced sensitivity to erlotinib, whereas treatment with HGF to directly induce phospho-Met resulted in erlotinib resistance. The level of endogenous phospho-c-Src inHNSCCcell lines was also significantly correlated with erlotinib resistance. Conclusions: Ligand-independent activation of c-Met contributes specifically to erlotinib resistance, not cetuximab resistance, in HNSCC with activated c-Src, where c-Met activation is more dependent on c-Src than on EGFR, providing an alternate survival pathway. Addition of a c-Met or c-Src inhibitor to erlotinib may increase efficacy of EGFR inhibition in patients with activated c-Src. © 2012 AACR.
Persistent Identifierhttp://hdl.handle.net/10722/194490
ISSN
2015 Impact Factor: 8.738
2015 SCImago Journal Rankings: 5.314
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorStabile, LP-
dc.contributor.authorHe, G-
dc.contributor.authorLui, VWY-
dc.contributor.authorHenry, C-
dc.contributor.authorGubish, CT-
dc.contributor.authorJoyce, S-
dc.contributor.authorQuesnelle, KM-
dc.contributor.authorSiegfried, JM-
dc.contributor.authorGrandis, JR-
dc.date.accessioned2014-01-30T03:32:39Z-
dc.date.available2014-01-30T03:32:39Z-
dc.date.issued2013-
dc.identifier.citationClinical Cancer Research, 2013, v. 19 n. 2, p. 380-392-
dc.identifier.issn1078-0432-
dc.identifier.urihttp://hdl.handle.net/10722/194490-
dc.description.abstractPurpose: Strategies to inhibit the EGF receptor (EGFR) using the tyrosine kinase inhibitor erlotinib have been associated with limited clinical efficacy in head and neck squamous cell carcinoma (HNSCC). Co-activation of alternative kinases may contribute to erlotinib resistance. Experimental Design: We generated HNSCC cells expressing dominant-active c-Src (DA-Src) to determine the contribution of c-Src activation to erlotinib response. Results: Expression of DA-Src conferred resistance to erlotinib in vitro and in vivo compared with vectortransfected control cells. Phospho-Met was strongly upregulated by DA-Src, and DA-Src cells did not produce hepatocyte growth factor (HGF). Knockdown of c-Met enhanced sensitivity to erlotinib in DA-Src cells in vitro, as did combining a c-Met or c-Src inhibitor with erlotinib. Inhibiting EGFR resulted in minimal reduction of phospho-Met in DA-Src cells, whereas complete phospho-Met inhibition was achieved by inhibiting c-Src. A c-Met inhibitor significantly sensitized DA-Src tumors to erlotinib in vivo, resulting in reduced Ki67 labeling and increased apoptosis. In parental cells, knockdown of endogenous c-Src enhanced sensitivity to erlotinib, whereas treatment with HGF to directly induce phospho-Met resulted in erlotinib resistance. The level of endogenous phospho-c-Src inHNSCCcell lines was also significantly correlated with erlotinib resistance. Conclusions: Ligand-independent activation of c-Met contributes specifically to erlotinib resistance, not cetuximab resistance, in HNSCC with activated c-Src, where c-Met activation is more dependent on c-Src than on EGFR, providing an alternate survival pathway. Addition of a c-Met or c-Src inhibitor to erlotinib may increase efficacy of EGFR inhibition in patients with activated c-Src. © 2012 AACR.-
dc.languageeng-
dc.relation.ispartofClinical Cancer Research-
dc.titleC-Src activation mediates erlotinib resistance in head and neck cancer by stimulating c-Met-
dc.typeArticle-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1158/1078-0432.CCR-12-1555-
dc.identifier.pmid23213056-
dc.identifier.scopuseid_2-s2.0-84872562509-
dc.identifier.volume19-
dc.identifier.issue2-
dc.identifier.spage380-
dc.identifier.epage392-
dc.identifier.isiWOS:000313739400009-

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