Winter GE , Rix U, Lissat A, Stukalov A, Mullner MK, Bennett KL, Colinge J, Nijman SM, Kubicek S, Kovar H , Kontny U, Superti-Furga G "MOLECULAR CANCER THERAPEUTICS OCT 2011"
Ewing's sarcoma is a pediatric cancer with the bone that's characterized through the expression of the chimeric transcription factor EWS-FLI1 that confers a highly malignant phenotype and final results from your chromosomal translocation t(11,22)(q24,q12). Inadequate general survival and pronounced long-term side effects associated with conventional chemotherapy necessitate the advancement of novel, targeted, therapeutic methods. We consequently performed a focused viability screen with 200 small molecule kinase inhibitors in two distinct Ewing's sarcoma cell lines. This resulted in the identification of many potential molecular intervention points.
Most notably, tozasertib (VX-680, MK-0457) shown unique nanomolar efficacy, which extended to other cell lines, but was distinct for Ewing's sarcoma. Moreover, tozasertib confirmed robust synergies using the chemotherapeutic drugs etoposide and doxorubicin, the current common agents for Ewing's sarcoma.
To identify the pertinent targets underlying the particular vulnerability towards tozasertib, we determined its cellular target profile by chemical proteomics. We identified twenty recognized and unfamiliar serine/threonine and tyrosine protein kinase targets. Additional target deconvolution and useful validation by RNAi confirmed simultaneous inhibition of Aurora kinases A and B to become responsible for that observed tozasertib sensitivity; thus revealing a new mechanism for focusing on Ewing's sarcoma.
We further corroborated our mobile observations with xenograft mouse designs.
In summary, the multilayered chemical biology approach introduced right here determined a certain vulnerability of Ewing's sarcoma to concomitant inhibition of Aurora kinases A and B by tozasertib and danusertib, that has the possible to become a new therapeutic alternative.
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