An allosteric pan-TEAD inhibitor blocks oncogenic YAP/TAZ signaling and overcomes KRAS G12C inhibitor resistance

被引：112

作者：

Hagenbeek, Thijs J. J. ^{[1
]}

Zbieg, Jason R. R. ^{[2
]}

Hafner, Marc ^{[3
]}

Mroue, Rana ^{[1
]}

Lacap, Jennifer A. A. ^{[4
]}

Sodir, Nicole M. M. ^{[4
]}

Noland, Cameron L. L. ^{[5
]}

Afghani, Shervin ^{[1
]}

Kishore, Ayush ^{[1
]}

Bhat, Kamakoti P. P. ^{[1
]}

Yao, Xiaosai ^{[3
]}

Schmidt, Stephen ^{[6
]}

Clausen, Saundra ^{[6
]}

Steffek, Micah ^{[6
]}

Lee, Wendy ^{[2
]}

Beroza, Paul ^{[2
]}

Martin, Scott ^{[1
]}

Lin, Eva ^{[1
]}

Fong, Rina ^{[5
]}

Di Lello, Paola ^{[5
]}

Kubala, Marta H. H. ^{[5
]}

Yang, Michelle N. -Y. ^{[4
]}

Lau, Jeffrey T. T. ^{[4
]}

Chan, Emily ^{[4
]}

Arrazate, Alfonso ^{[4
]}

An, Le ^{[7
]}

Levy, Elizabeth ^{[7
]}

Lorenzo, Maria N. N. ^{[8
]}

Lee, Ho-June ^{[1
]}

Pham, Trang H. H. ^{[1
]}

Modrusan, Zora ^{[9
]}

Zang, Richard ^{[10
]}

Chen, Yi-Chen ^{[10
]}

Kabza, Michal ^{[11
]}

Ahmed, Musaddeque ^{[12
]}

Li, Jason ^{[3
]}

Chang, Matthew T. T. ^{[3
]}

Maddalo, Danilo ^{[4
]}

Evangelista, Marie ^{[1
]}

Ye, Xin ^{[1
]}

Crawford, James J. J. ^{[2
]}

Dey, Anwesha ^{[1
]}

机构：

[1] Dept Discovery Oncol, Genentech, San Francisco, CA 94080 USA

[2] Genentech Inc, Dept Discovery Chem, San Francisco, CA 94080 USA

[3] Genentech Inc, Dept Oncol Bioinformat, San Francisco, CA USA

[4] Genentech Inc, Dept Translat Oncol, San Francisco, CA USA

[5] Genentech Inc, Dept Struct Biol, San Francisco, CA USA

[6] Genentech Inc, Dept Biochem & Cellular Pharmacol, San Francisco, CA USA

[7] Genentech Inc, Dept Small Mol Pharmaceut Sci, San Francisco, CA USA

[8] Genentech Inc, Dept Prot Chem, San Francisco, CA USA

[9] Genentech Inc, Dept Microchem Prote & Lipid, San Francisco, CA USA

[10] Genentech Inc, Dept Drug Metab & Pharmacokinet, San Francisco, CA USA

[11] Roche Polska, Warsaw, Poland

[12] Roche Canada, Mississauga, ON, Canada

来源：

NATURE CANCER | 2023年 / 4卷 / 06期

关键词：

HIPPO PATHWAY; PROMOTES RESISTANCE; YAP; PROTEIN; EXPRESSION; GROWTH;

D O I：

10.1038/s43018-023-00577-0

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 [肿瘤学];

摘要：

Hagenbeek et al. identify a small-molecule pan-TEAD inhibitor that blocks the interaction between YAP/TAZ and TEAD proteins. They demonstrate that treatment with the inhibitor leads to antitumor activity and can synergize with KRAS G12C inhibition. The Hippo pathway is a key growth control pathway that is conserved across species. The downstream effectors of the Hippo pathway, YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif), are frequently activated in cancers to drive proliferation and survival. Based on the premise that sustained interactions between YAP/TAZ and TEADs (transcriptional enhanced associate domain) are central to their transcriptional activities, we discovered a potent small-molecule inhibitor (SMI), GNE-7883, that allosterically blocks the interactions between YAP/TAZ and all human TEAD paralogs through binding to the TEAD lipid pocket. GNE-7883 effectively reduces chromatin accessibility specifically at TEAD motifs, suppresses cell proliferation in a variety of cell line models and achieves strong antitumor efficacy in vivo. Furthermore, we uncovered that GNE-7883 effectively overcomes both intrinsic and acquired resistance to KRAS (Kirsten rat sarcoma viral oncogene homolog) G12C inhibitors in diverse preclinical models through the inhibition of YAP/TAZ activation. Taken together, this work demonstrates the activities of TEAD SMIs in YAP/TAZ-dependent cancers and highlights their potential broad applications in precision oncology and therapy resistance.

引用

页码：812 / +

页数：30

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