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FBXL2 counteracts Grp94 to destabilize EGFR and inhibit EGFR-driven NSCLC growth

Author

Listed:
  • Mengmeng Niu

    (Ministry of Education, College of Life Sciences, Sichuan University)

  • Jing Xu

    (Ministry of Education, College of Life Sciences, Sichuan University)

  • Yang Liu

    (Ministry of Education, College of Life Sciences, Sichuan University)

  • Yuhuang Li

    (Ministry of Education, College of Life Sciences, Sichuan University)

  • Tao He

    (Ministry of Education, College of Life Sciences, Sichuan University)

  • Liangping Ding

    (Ministry of Education, College of Life Sciences, Sichuan University)

  • Yajun He

    (Ministry of Education, College of Life Sciences, Sichuan University)

  • Yong Yi

    (Ministry of Education, College of Life Sciences, Sichuan University)

  • Fengtian Li

    (Ministry of Education, College of Life Sciences, Sichuan University)

  • Rongtian Guo

    (Ministry of Education, College of Life Sciences, Sichuan University)

  • Ya Gao

    (Ministry of Education, College of Life Sciences, Sichuan University)

  • Rui Li

    (Ministry of Education, College of Life Sciences, Sichuan University)

  • Luping Li

    (Ministry of Education, College of Life Sciences, Sichuan University)

  • Mengyuan Fu

    (Ministry of Education, College of Life Sciences, Sichuan University)

  • Qingyong Hu

    (Ministry of Education, College of Life Sciences, Sichuan University)

  • Yangkun Luo

    (Ministry of Education, College of Life Sciences, Sichuan University)

  • Chunyan Zhang

    (Ministry of Education, College of Life Sciences, Sichuan University)

  • Kewei Qin

    (Ministry of Education, College of Life Sciences, Sichuan University)

  • Jianqiao Yi

    (Ministry of Education, College of Life Sciences, Sichuan University)

  • Shuhan Yu

    (Ministry of Education, College of Life Sciences, Sichuan University)

  • Jian Yang

    (Ministry of Education, College of Life Sciences, Sichuan University)

  • Hu Chen

    (Ministry of Education, College of Life Sciences, Sichuan University)

  • Liang Wang

    (Ministry of Education, College of Life Sciences, Sichuan University)

  • Zhonghan Li

    (Ministry of Education, College of Life Sciences, Sichuan University)

  • Biao Dong

    (State Key Laboratory of Biotherapy, West China Hospital, Sichuan University)

  • Shiqian Qi

    (State Key Laboratory of Biotherapy, West China Hospital, Sichuan University)

  • Liang Ouyang

    (State Key Laboratory of Biotherapy, West China Hospital, Sichuan University)

  • Yujun Zhang

    (Ministry of Education, College of Life Sciences, Sichuan University)

  • Yang Cao

    (Ministry of Education, College of Life Sciences, Sichuan University)

  • Zhi-Xiong Jim Xiao

    (Ministry of Education, College of Life Sciences, Sichuan University
    State Key Laboratory of Biotherapy, West China Hospital, Sichuan University)

Abstract

Abnormal activation of epidermal growth factor receptor (EGFR) drives non-small cell lung cancer (NSCLC) development. EGFR mutations-mediated resistance to tyrosine-kinase inhibitors (TKIs) is a major hurdle for NSCLC treatment. Here, we show that F-box protein FBXL2 targets EGFR and EGFR TKI-resistant mutants for proteasome-mediated degradation, resulting in suppression of EGFR-driven NSCLC growth. Reduced FBXL2 expression is associated with poor clinical outcomes of NSCLC patients. Furthermore, we show that glucose-regulated protein 94 (Grp94) protects EGFR from degradation via blockage of FBXL2 binding to EGFR. Moreover, we have identified nebivolol, a clinically used small molecule inhibitor, that can upregulate FBXL2 expression to inhibit EGFR-driven NSCLC growth. Nebivolol in combination with osimertinib or Grp94-inhibitor-1 exhibits strong inhibitory effects on osimertinib-resistant NSCLC. Together, this study demonstrates that the FBXL2-Grp94-EGFR axis plays a critical role in NSCLC development and suggests that targeting FBXL2-Grp94 to destabilize EGFR may represent a putative therapeutic strategy for TKI-resistant NSCLC.

Suggested Citation

  • Mengmeng Niu & Jing Xu & Yang Liu & Yuhuang Li & Tao He & Liangping Ding & Yajun He & Yong Yi & Fengtian Li & Rongtian Guo & Ya Gao & Rui Li & Luping Li & Mengyuan Fu & Qingyong Hu & Yangkun Luo & Chu, 2021. "FBXL2 counteracts Grp94 to destabilize EGFR and inhibit EGFR-driven NSCLC growth," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-26222-x
    DOI: 10.1038/s41467-021-26222-x
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    References listed on IDEAS

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    1. Yong Jia & Cai-Hong Yun & Eunyoung Park & Dalia Ercan & Mari Manuia & Jose Juarez & Chunxiao Xu & Kevin Rhee & Ting Chen & Haikuo Zhang & Sangeetha Palakurthi & Jaebong Jang & Gerald Lelais & Michael , 2016. "Overcoming EGFR(T790M) and EGFR(C797S) resistance with mutant-selective allosteric inhibitors," Nature, Nature, vol. 534(7605), pages 129-132, June.
    2. Shafi Kuchay & Carlotta Giorgi & Daniele Simoneschi & Julia Pagan & Sonia Missiroli & Anita Saraf & Laurence Florens & Michael P. Washburn & Ana Collazo-Lorduy & Mireia Castillo-Martin & Carlos Cordon, 2017. "PTEN counteracts FBXL2 to promote IP3R3- and Ca2+-mediated apoptosis limiting tumour growth," Nature, Nature, vol. 546(7659), pages 554-558, June.
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    Cited by:

    1. Yuxiu Xu & Xin Li & Fang Cheng & Bao Zhao & Min Fang & Zihai Li & Songdong Meng, 2024. "Heat shock protein gp96 drives natural killer cell maturation and anti-tumor immunity by counteracting Trim28 to stabilize Eomes," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    2. Kewei Qin & Shuhan Yu & Yang Liu & Rongtian Guo & Shiya Guo & Junjie Fei & Yuemeng Wang & Kaiyuan Jia & Zhiqiang Xu & Hu Chen & Fengtian Li & Mengmeng Niu & Mu-Shui Dai & Lunzhi Dai & Yang Cao & Yujun, 2023. "USP36 stabilizes nucleolar Snail1 to promote ribosome biogenesis and cancer cell survival upon ribotoxic stress," Nature Communications, Nature, vol. 14(1), pages 1-15, December.

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