Levels of active tyrosine kinase receptor determine the tumor response to Zalypsis

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dc.contributor.author Moneo, Victoria
dc.contributor.author Serelde, Beatriz G.
dc.contributor.author Blanco-Aparicio, Carmen
dc.contributor.author Díaz-Uriarte, Ramón
dc.contributor.author Avilés, Pablo Leyton
dc.contributor.author Santamaría, Gemma
dc.contributor.author Tercero, Juan Carlos
dc.contributor.author Cuevas, Carmen Del Maria
dc.contributor.author Carnero, Amancio
dc.date.accessioned 2014-10-07T13:12:11Z
dc.date.available 2014-10-07T13:12:11Z
dc.date.issued 2014-04-23
dc.identifier.citation BMC Cancer 14 (2014): 281 en_US
dc.identifier.issn 1471-2407 es_ES
dc.identifier.uri http://hdl.handle.net/10486/662083
dc.description.abstract Background: Zalypsis® is a marine compound in phase II clinical trials for multiple myeloma, cervical and endometrial cancer, and Ewing’s sarcoma. However, the determinants of the response to Zalypsis are not well known. The identification of biomarkers for Zalypsis activity would also contribute to broaden the spectrum of tumors by selecting those patients more likely to respond to this therapy. Methods: Using in vitro drug sensitivity data coupled with a set of molecular data from a panel of sarcoma cell lines, we developed molecular signatures that predict sensitivity to Zalypsis. We verified these results in culture and in vivo xenograft studies. Results: Zalypsis resistance was dependent on the expression levels of PDGFRα or constitutive phosphorylation of c-Kit, indicating that the activation of tyrosine kinase receptors (TKRs) may determine resistance to Zalypsis. To validate our observation, we measured the levels of total and active (phosphorylated) forms of the RTKs PDGFRα/β, c-Kit, and EGFR in a new panel of diverse solid tumor cell lines and found that the IC50 to the drug correlated with RTK activation in this new panel. We further tested our predictions about Zalypsis determinants for response in vivo in xenograft models. All cells lines expressing low levels of RTK signaling were sensitive to Zalypsis in vivo, whereas all cell lines except two with high levels of RTK signaling were resistant to the drug. Conclusions: RTK activation might provide important signals to overcome the cytotoxicity of Zalypsis and should be taken into consideration in current and future clinical trials en_US
dc.description.sponsorship The AC lab was supported by grants to from the Spanish Ministry of Economy and Competitivity, ISCIII (Fis: PI12/00137, RTICC: RD12/0036/0028), Consejeria de Ciencia e Innovacion (CTS-6844), and Consejeria de Salud of the Junta de Andalucia (PI-0135-2010 and PI-0306-2012) en_US
dc.format.extent 10 pag. es_ES
dc.format.mimetype application/pdf en
dc.language.iso eng es_ES
dc.publisher BioMed Central en_US
dc.relation.ispartof BMC Cancer en_US
dc.rights © 2014 Moneo et al. es_ES
dc.subject.other Antitumor compound en_US
dc.subject.other Marine compound en_US
dc.subject.other PDGFR en_US
dc.subject.other Tyrosine kinase receptors en_US
dc.subject.other Zalypsis en_US
dc.title Levels of active tyrosine kinase receptor determine the tumor response to Zalypsis en_US
dc.type article en
dc.subject.eciencia Medicina es_ES
dc.relation.publisherversion http://dx.doi.org/10.1186/1471-2407-14-281 es_ES
dc.identifier.doi 10.1186/1471-2407-14-281 es_ES
dc.identifier.publicationfirstpage 281 es_ES
dc.identifier.publicationvolume 14 es_ES
dc.type.version info:eu-repo/semantics/publishedVersion en
dc.rights.cc Reconocimiento es_ES
dc.rights.accessRights openAccess en


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