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Pharmacological blockade of TEAD–YAP reveals its therapeutic limitation in cancer cells

Author

Listed:
  • Yang Sun

    (Harvard Medical School, Charlestown
    Xuzhou Medical University)

  • Lu Hu

    (Harvard Medical School, Charlestown)

  • Zhipeng Tao

    (Harvard Medical School, Charlestown)

  • Gopala K. Jarugumilli

    (Harvard Medical School, Charlestown)

  • Hannah Erb

    (Harvard Medical School, Charlestown)

  • Alka Singh

    (University of Massachusetts Chan Medical School, Worcester)

  • Qi Li

    (University of Massachusetts Chan Medical School, Worcester)

  • Jennifer L. Cotton

    (University of Massachusetts Chan Medical School, Worcester)

  • Patricia Greninger

    (Harvard Medical School, Charlestown)

  • Regina K. Egan

    (Harvard Medical School, Charlestown)

  • Y. Tony Ip

    (University of Massachusetts Chan Medical School, Worcester)

  • Cyril H. Benes

    (Harvard Medical School, Charlestown)

  • Jianwei Che

    (Dana Farber Cancer Institute, and Harvard Medical School, Boston)

  • Junhao Mao

    (University of Massachusetts Chan Medical School, Worcester)

  • Xu Wu

    (Harvard Medical School, Charlestown)

Abstract

Targeting TEAD autopalmitoylation has been proposed as a therapeutic approach for YAP-dependent cancers. Here we show that TEAD palmitoylation inhibitor MGH-CP1 and analogues block cancer cell “stemness”, organ overgrowth and tumor initiation in vitro and in vivo. MGH-CP1 sensitivity correlates significantly with YAP-dependency in a large panel of cancer cell lines. However, TEAD inhibition or YAP/TAZ knockdown leads to transient inhibition of cell cycle progression without inducing cell death, undermining their potential therapeutic utilities. We further reveal that TEAD inhibition or YAP/TAZ silencing leads to VGLL3-mediated transcriptional activation of SOX4/PI3K/AKT signaling axis, which contributes to cancer cell survival and confers therapeutic resistance to TEAD inhibitors. Consistently, combination of TEAD and AKT inhibitors exhibits strong synergy in inducing cancer cell death. Our work characterizes the therapeutic opportunities and limitations of TEAD palmitoylation inhibitors in cancers, and uncovers an intrinsic molecular mechanism, which confers potential therapeutic resistance.

Suggested Citation

  • Yang Sun & Lu Hu & Zhipeng Tao & Gopala K. Jarugumilli & Hannah Erb & Alka Singh & Qi Li & Jennifer L. Cotton & Patricia Greninger & Regina K. Egan & Y. Tony Ip & Cyril H. Benes & Jianwei Che & Junhao, 2022. "Pharmacological blockade of TEAD–YAP reveals its therapeutic limitation in cancer cells," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34559-0
    DOI: 10.1038/s41467-022-34559-0
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    References listed on IDEAS

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    1. Mathew J. Garnett & Elena J. Edelman & Sonja J. Heidorn & Chris D. Greenman & Anahita Dastur & King Wai Lau & Patricia Greninger & I. Richard Thompson & Xi Luo & Jorge Soares & Qingsong Liu & Francesc, 2012. "Systematic identification of genomic markers of drug sensitivity in cancer cells," Nature, Nature, vol. 483(7391), pages 570-575, March.
    2. Shi Jiao & Chuanchuan Li & Qian Hao & Haofei Miao & Lei Zhang & Lin Li & Zhaocai Zhou, 2017. "VGLL4 targets a TCF4–TEAD4 complex to coregulate Wnt and Hippo signalling in colorectal cancer," Nature Communications, Nature, vol. 8(1), pages 1-13, April.
    3. Shenghong Ma & Tracy Tang & Gary Probst & Andrei Konradi & Chunyu Jin & Fulong Li & J. Silvio Gutkind & Xiang-Dong Fu & Kun-Liang Guan, 2022. "Transcriptional repression of estrogen receptor alpha by YAP reveals the Hippo pathway as therapeutic target for ER+ breast cancer," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
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