清大生醫學院學士後醫學系王慧菁教授（中間）與研究團隊成員

Associate Professor Hui-Ching Wang of School of Medicine, College of Life Sciences and Medicine, National Tsing Hua University, with research team member.

論文標題Paper Title

KIF2C promotes paclitaxel resistance by depolymerizing polyglutamylated microtubules

學術期刊刊名Journal Name

Developmental Cell

研究團隊 Research Team

主持人Principle Investigator：

王慧菁教授Hui-Ching Wang, Professor

國立清華大學生命科學暨醫學院 學士後醫學系/分子與細胞生物研究所

School of Medicine

Institute of Molecular and Cellular Biology

College of Life Sciences and Medicine (CLSM), National Tsing Hua University (NTHU).

參與者Participants:：

孫玉珠 教授 Yuh-Ju Sun, Professor

國立清華大學生命科學暨醫學院 生物資訊與結構研究所

Institute of Bioinformatics and Structural Biology, College of Life Sciences and Medicine, NTHU

謝興邦 所長 Hsing-Pang Hsieh

國衛院 生技與藥物研究所

Institute of Biotechnology and Pharmaceutical Research , National Health Research Institutes

郭靜娟 博士 Ching-Chuan Kuo

國衛院 生技與藥物研究所

Institute of Biotechnology and Pharmaceutical Research , National Health Research Institutes

摘要

Abstract

三陰性乳癌（TNBC）約占所有乳癌之 10–15%，因缺乏荷爾蒙受體與 HER2 表現，臨床仍以紫杉醇為主要化療藥物。然而超過四成患者於治療後復發，並伴隨多重抗藥性，陷入無藥可醫困境。本專案旨在解析紫杉醇抗藥性的分子機制，並開發精準輔助療法。研究團隊發現微管解聚驅動蛋白 KIF2C 在抗藥性腫瘤中大量表現，能優先解聚被「多麩胺酸化（polyglutamylation）」修飾、被紫杉醇穩定的微管，使癌細胞逃脫有絲分裂災難。透過跨機構整合（結構生物學、藥物化學、藥理毒理），本團隊成功研發全球首創（first-in-class）兼具細胞穿透性與細胞毒殺活性的 KIF2C 小分子抑制劑 7S9，期能為復發轉移性乳癌與婦科癌症患者帶來新治療曙光。

Triple-negative breast cancer (TNBC) constitutes 10–15% of all breast cancers and lacks targeted therapies, leaving paclitaxel as the chemotherapeutic cornerstone. Yet over 40% of patients relapse with multidrug resistance and limited options. This project elucidates the molecular mechanism underlying paclitaxel resistance and translates the discovery into a precision adjuvant therapy. We demonstrate that the kinesin-13 microtubule depolymerase KIF2C is upregulated in resistant TNBC and selectively depolymerizes polyglutamylated microtubules stabilized by paclitaxel, enabling cancer cells to escape mitotic catastrophe. Through interdisciplinary collaboration spanning structural biology, medicinal chemistry, and pharmacology/toxicology, we developed 7S9—the first-in-class cell-permeable, cytotoxic KIF2C inhibitor—opening a new therapeutic window for relapsed metastatic breast cancer and women's gynecological malignancies.

研究成果Result/Contributions

本專案聚焦解析三陰性乳癌（TNBC）紫杉醇抗藥性的分子機制，並轉譯為臨床可用的精準療法。重要研究成果如下：

1. 抗藥機制的關鍵發現：團隊整合臨床大數據與系統生物學分析，自 2017 年起首先指出微管解聚驅動蛋白 KIF2C 與 TNBC 預後密切相關。隨後建立紫杉醇抗藥性 TNBC 細胞株，證實 KIF2C 在抗藥細胞中大量表現，能優先解聚被「多麩胺酸化（polyglutamylation）」修飾的穩定微管，瓦解紫杉醇所誘發的微管固化效應，使癌細胞逃脫有絲分裂災難。此一發現首度將「微管修飾的可塑性」定義為可標靶的抗藥機制。

2. 新藥開發成果：透過跨領域合作—結構生物學（孫玉珠教授）、藥物化學（國衛院謝興邦所長、林書玉博士）、藥理毒理（國衛院郭靜娟博士）—團隊完成大規模化合物篩選與多輪小分子優化，研發出全球首創（first-in-class）兼具細胞穿透與細胞毒殺活性的 KIF2C 小分子抑制劑 7S9。7S9 與紫杉醇併用可提升療效達 200 倍；與其他微管藥物併用具 20 倍以上加乘效果，動物試驗中亦展現顯著抗腫瘤效果，顯示其作為廣效化療增敏劑的潛力。

3. 臨床轉譯與產業化：相關成果已取得中華民國發明專利（202523325，2025 年核准），美國等專利仍在審查中。本論文第一作者包原韶於 2024 年帶領團隊成立「醫莉鎂生醫」新創公司，進駐第十七屆清大創業車庫，並獲國科會 114 年度科研創業計畫萌芽案支持，目標推進臨床前試驗。除三陰性乳癌外，KIF2C 在卵巢癌、子宮內膜癌、子宮頸癌等女性婦科腫瘤亦高度表現，未來臨床適應症可進一步擴展至女性癌症。

4. 學術與社會肯定：本論文於 2025 年 8 月發表於頂尖期刊 Developmental Cell並獲選為當期封面故事。團隊另榮獲 2025 國家新創獎、2025 乳癌防治基金會優秀論文獎、2024 未來科技獎、2024 與 2025 全國精準健康產業創新創業競賽智慧健康組金獎、2025 全國生醫創新創業競賽金獎等多項殊榮，展現本研究在學術原創與產業轉譯的雙重價值。

This project elucidates the molecular mechanism of paclitaxel resistance in triple-negative breast cancer (TNBC) and translates the discovery into a precision therapy.

1. Mechanistic breakthrough: Integrating clinical big data with systems biology since 2017, the team first identified KIF2C as prognostically linked to TNBC. Using paclitaxel-resistant TNBC cell lines, we showed that KIF2C is upregulated in resistant cells and selectively depolymerizes polyglutamylated microtubules stabilized by paclitaxel, enabling cancer cells to escape mitotic catastrophe. This work establishes microtubule-modification plasticity as a druggable resistance mechanism.

2. Drug development: Through interdisciplinary collaboration—structural biology (Prof. Y.J. Sun), medicinal chemistry (NHRI Director H.P. Hsieh & Dr. S.Y. Lin), pharmacology/toxicology (NHRI Dr. C.C. Kuo)—we developed 7S9, the first-in-class cell-permeable, cytotoxic KIF2C inhibitor. 7S9 enhances paclitaxel efficacy by 200-fold and exhibits >20-fold synergy with other microtubule agents, with significant anti-tumor activity in animal models—demonstrating broad chemo-sensitizer potential.

3. Translation & commercialization: A Taiwan invention patent has been granted (202523325, 2025); US and other patents pending. First author Y.S. Pao founded YiLiMei BioMed in 2024, joined NTHU Garage Cohort 17, and received NSTC 2026 Startup Sprout funding to advance preclinical trials. Beyond TNBC, KIF2C is highly expressed in ovarian, endometrial, and cervical cancers—suggesting broad applicability across women's malignancies.

4. Recognition: Published in Developmental Cell and featured as the August 2025 Cover Story. Awards include the 2025 National Innovation Award, 2025 Taiwan Breast Cancer Foundation Outstanding Paper Award, 2024 Future Tech Award, and gold prizes at the 2024/2025 National Innovation & Entrepreneurship Competition in Precision Health, demonstrating the dual academic and translational value of this research.

論文連結 Paper Link

論文 DOI 連結（Developmental Cell, 2025）

https://doi.org/10.1016/j.devcel.2025.03.004

PubMed

https://pubmed.ncbi.nlm.nih.gov/40157365/

醫莉鎂生醫（YiLiMei BioMed）相關介紹（清大創業車庫第十七屆團隊）

國科會 114 年度科研創業計畫萌芽案

1.台灣新視野-媒體報導

https://www.youtube.com/watch?v=xo2R026Nv8Y

2.環球生技

https://news.gbimonthly.com/tw/article/show.php?num=78370

3.國衛院

https://www.nhri.edu.tw/news/more?id=ffe9b5f453e34794b83810407db4d69b

4.經濟日報

https://money.udn.com/money/story/5612/8848344

5.北美智權

https://naipnews.naipo.com/27436/