2. Academic Validation
  3. KIF2C promotes paclitaxel resistance by depolymerizing polyglutamylated microtubules

KIF2C promotes paclitaxel resistance by depolymerizing polyglutamylated microtubules

  • Dev Cell. 2025 Mar 25:S1534-5807(25)00151-0. doi: 10.1016/j.devcel.2025.03.004.
Yuan-Shao Pao 1,  Kuan-Ju Liao 2,  Ya-Chia Shiau 3,  Ming-Hong Chao 1,  Mu-Chun Li 4,  Li-Mei Lin 5,  Hsin-Huei Chang 5,  Hung-Wei Yeh 2,  Yi-Ju Chen 6,  Yu-Ting Chiu 1,  Max Yu-Chen Pan 1,  Yu-Hsuan Chang 1,  Shih-Yu Shen 1,  Shu-Yu Lin 5,  Hui-Chun Cheng 2,  Yu-Chun Lin 7,  Yuh-Ju Sun 8,  Ching-Chuan Kuo 9,  Hsing-Pang Hsieh 10,  Lily Hui-Ching Wang 11
Affiliations

Affiliations

  • 1 Institute of Molecular and Cellular Biology, National Tsing Hua University, Hsinchu City 300044, Taiwan.
  • 2 Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu City 300044, Taiwan.
  • 3 Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 350401, Taiwan; Department of Chemistry, National Tsing Hua University, Hsinchu City 300044, Taiwan.
  • 4 Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 350401, Taiwan; Biomedical Translation Research Center, Academia Sinica, Taipei City 115202, Taiwan.
  • 5 Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 350401, Taiwan.
  • 6 Institute of Chemistry, Academia Sinica, Taipei City 115202, Taiwan.
  • 7 Institute of Molecular Medicine, National Tsing Hua University, Hsinchu City 300044, Taiwan; Department of Medical Sciences, National Tsing Hua University, Hsinchu City 300044, Taiwan.
  • 8 Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu City 300044, Taiwan. Electronic address: yjsun@life.nthu.edu.tw.
  • 9 Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 350401, Taiwan. Electronic address: cckuo@nhri.edu.tw.
  • 10 Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 350401, Taiwan; Department of Chemistry, National Tsing Hua University, Hsinchu City 300044, Taiwan; Biomedical Translation Research Center, Academia Sinica, Taipei City 115202, Taiwan. Electronic address: hphsieh@nhri.edu.tw.
  • 11 Institute of Molecular and Cellular Biology, National Tsing Hua University, Hsinchu City 300044, Taiwan; Department of Medical Sciences, National Tsing Hua University, Hsinchu City 300044, Taiwan; School of Medicine, National Tsing Hua University, Hsinchu City 300044, Taiwan. Electronic address: lilywang@life.nthu.edu.tw.
PMID: 40157365 DOI: 10.1016/j.devcel.2025.03.004
Abstract

The long-term effectiveness of paclitaxel is limited by chemoresistance. In this study, we elucidate the molecular mechanism by which Kinesin family member 2C (KIF2C), a well-known microtubule depolymerase, contributes to the development of chemoresistance in triple-negative breast Cancer (TNBC). We observed elevated levels of KIF2C, tubulin tyrosination, and polyglutamylation in human and mouse breast Cancer cells resistant to paclitaxel. Additionally, these chemoresistant cells possessed cross-resistance to diverse microtubule-targeting agents (MTAs). We demonstrated that KIF2C preferentially depolymerizes polyglutamylated tubulin, even in the presence of paclitaxel. To counter this, we developed 7S9, a chemical inhibitor of KIF2C, that prohibits the dissociation of KIF2C from microtubules. The combination of 7S9 and paclitaxel significantly reduced tumorigenesis in chemoresistant TNBC model in mice. Moreover, 7S9 diminished Cancer cell chemoresistance to several clinically available MTAs. Our findings elucidate the molecular mechanism of KIF2C-mediated chemoresistance and highlight KIF2C as a promising target for combating cross-resistance in TNBC.

Keywords

KIF2C; MCAK; breast cancer; chemoresistance; cross-resistance; kinesin-13; microtubule; paclitaxel; polyglutamylation; triple-negative.

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