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

BMC Cancer

Victoria Moneo⁴  Beatriz G Serelde²  Carmen Blanco-Aparicio²  Ramon Diaz-Uriarte³  Pablo Avilés⁴  Gemma Santamaría⁴  Juan C Tercero⁴  Carmen Cuevas⁴  Amancio Carnero¹ 

[1] Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocio, Edificio IBIS, Consejo Superior de Investigaciones Cientificas, Avda. Manuel Siurot s/n., Sevilla 41013, Spain

[2] Experimental Therapeutics Programme, Spanish National Cancer Center (CNIO), Madrid, Spain

[3] Structural Biology and Biocomputing Programme, Spanish National Cancer Center (CNIO), Madrid, Spain

[4] PharmaMar R & D, Madrid, Spain

关键词: Antitumor compound;    Tyrosine kinase receptors;    PDGFR;    Marine compound;    Zalypsis;   

Others  :  858876
DOI  :  10.1186/1471-2407-14-281

 received in 2013-09-09, accepted in 2014-04-08,  发布年份 2014

【 摘 要 】

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.

【 授权许可】

   
2014 Moneo et al.; licensee BioMed Central Ltd.

【 图 表 】

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