Instruct: Identify the main category of Biorxiv papers based on the titles and abstracts
Query: TK216 targets microtubules in Ewing sarcoma cells Ewing sarcoma (EWS) is a pediatric malignancy driven by the EWSR1-FLI1 fusion protein formed by the chromosomal translocation t(11;22). The small molecule TK216 was developed as a first-in-class direct EWSR1-FLI1 inhibitor and is in phase II clinical trials in combination with vincristine for EWS patients. However, TK216 exhibits anti-cancer activity against cancer cell lines and xenografts that do not express EWSR1-FLI1, and the mechanism underlying cytotoxicity remains unresolved. We apply a forward genetics screening platform utilizing engineered hypermutation in EWS cell lines and identify recurrent mutations in TUBA1B, encoding -tubulin, that prove sufficient to drive resistance to TK216. Using reconstituted microtubule (MT) polymerization in vitro and cell-based chemical probe competition assays, we demonstrate that TK216 acts as an MT destabilizing agent. This work defines the mechanism of cytotoxicity of TK216, explains the synergy observed with vincristine, and calls for a reexamination of ongoing clinical trials with TK216.
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The categories of this paper are: cell
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The categories of this paper are: plant
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The categories of this paper are: immunology
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The categories of this paper are: evolutionary
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The categories of this paper are: toxicology
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The categories of this paper are: biophysics
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The categories of this paper are: systems
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The categories of this paper are: pharmacology
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The categories of this paper are: synthetic
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The categories of this paper are: paleontology
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The categories of this paper are: neuroscience
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The categories of this paper are: ecology
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The categories of this paper are: scientific
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The categories of this paper are: and
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The categories of this paper are: behavior
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The categories of this paper are: pathology