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TK216 targets microtubules in Ewing sarcoma cells

Juan Manuel Povedano1, Vicky Li1, Katherine E Lake1

  • 1Department of Internal Medicine, Division of Endocrinology, University of Texas Southwestern Medical Center, Dallas, TX 75390 USA; Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390 USA.

Cell Chemical Biology
|July 8, 2022
PubMed

Insights

The small molecule TK216, investigated for Ewing sarcoma, destabilizes microtubules, explaining its anti-cancer effects beyond its intended target. This discovery clarifies its mechanism and potential clinical applications.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Ewing sarcoma (EWS) is a pediatric cancer driven by the EWSR1-FLI1 fusion protein.
  • TK216 is a novel inhibitor targeting EWSR1-FLI1, currently in Phase II clinical trials for EWS.
  • The precise mechanism of TK216's cytotoxicity, especially in non-EWSR1-FLI1 expressing cells, remained unclear.

Purpose of the Study:

  • To elucidate the unresolved mechanism of TK216's anti-cancer activity.
  • To identify genetic factors conferring resistance to TK216.
  • To understand the basis for TK216's synergy with vincristine.

Main Methods:

  • Utilized a forward-genetics screening platform with engineered hypermutation in EWS cell lines.
  • Identified mutations in TUBA1B (encoding ⍺-tubulin) associated with TK216 resistance.
  • Performed in vitro microtubule (MT) polymerization assays and cell-based chemical probe competition assays.

Main Results:

  • Discovered recurrent TUBA1B mutations conferring resistance to TK216.
  • Demonstrated that TK216 functions as a microtubule (MT) destabilizing agent.
  • Established the mechanism of TK216 cytotoxicity and its synergy with vincristine.

Conclusions:

  • TK216's primary mechanism involves microtubule destabilization, not solely EWSR1-FLI1 inhibition.
  • This finding explains TK216's efficacy in a broader range of cancers and its synergy with vincristine.
  • Recommends re-evaluation of ongoing clinical trials involving TK216 based on its clarified mechanism of action.
Keywords:
Ewing sarcomaONCT-216TK216YK-4-279microtubulestarget identification

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