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

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 Mao () and Xu Wu ()
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Yang Sun: Harvard Medical School, Charlestown
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

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-34559-0

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