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Levels of active tyrosine kinase receptor determine the tumor response to Zalypsis
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Levels of active tyrosine kinase receptor determine the tumor response to Zalypsis
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Journal Article
Levels of active tyrosine kinase receptor determine the tumor response to Zalypsis
2014
Overview
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.
Publisher
BioMed Central,Springer Nature B.V
Subject
/ Biomedical and Life Sciences
/ DNA
/ Experimental therapeutics and drug development
/ Gene Expression Regulation, Neoplastic
/ Health Promotion and Disease Prevention
/ Humans
/ Oncology
/ Proto-Oncogene Proteins c-kit - biosynthesis
/ Receptor, Epidermal Growth Factor - biosynthesis
/ Receptor, Platelet-Derived Growth Factor alpha - biosynthesis
/ Receptor, Platelet-Derived Growth Factor alpha - genetics
/ Receptor, Platelet-Derived Growth Factor beta - biosynthesis
/ Receptor, Platelet-Derived Growth Factor beta - genetics
/ RNA, Messenger - biosynthesis
/ Rodents
/ Studies
/ Tetrahydroisoquinolines - administration & dosage
/ Tumors
