Cooperation between the Hippo and MAPK pathway activation drives acquired resistance to TEAD inhibition

Sayantanee Paul, Thijs J. Hagenbeek, Julien Tremblay, Vasumathi Kameswaran, Christy Ong, Chad Liu, Alissa D. Guarnaccia, James A. Mondo, Peter L. Hsu, Noelyn M. Kljavin, Bartosz Czech, Janina Smola, Dieu An H. Nguyen, Jennifer A. Lacap, Trang H. Pham, Yuxin Liang, Robert A. Blake, Luca Gerosa, Matthew Grimmer, Shiqi Xie, Bence Daniel, Xiaosai Yao () and Anwesha Dey ()
Additional contact information
Sayantanee Paul: Genentech Inc
Thijs J. Hagenbeek: Genentech Inc
Julien Tremblay: Genentech Inc
Vasumathi Kameswaran: Genentech Inc
Christy Ong: Genentech Inc
Chad Liu: Genentech Inc
Alissa D. Guarnaccia: Genentech Inc
James A. Mondo: Hoffman-La Roche Canada
Peter L. Hsu: Genentech Inc
Noelyn M. Kljavin: Genentech Inc
Bartosz Czech: Roche Global IT Solution Centre
Janina Smola: Roche Global IT Solution Centre
Dieu An H. Nguyen: Genentech Inc
Jennifer A. Lacap: Genentech Inc
Trang H. Pham: Genentech Inc
Yuxin Liang: Genentech Inc
Robert A. Blake: Genentech Inc
Luca Gerosa: Genentech Inc
Matthew Grimmer: Genentech Inc
Shiqi Xie: Genentech Inc
Bence Daniel: Genentech Inc
Xiaosai Yao: Genentech Inc
Anwesha Dey: Genentech Inc

Nature Communications, 2025, vol. 16, issue 1, 1-21

Abstract: Abstract TEAD (transcriptional enhanced associate domain) transcription factors (TEAD1-4) serve as the primary effectors of the Hippo signaling pathway in various cancers. Targeted therapy leads to the emergence of resistance and the underlying mechanism of resistance to TEAD inhibition in cancers is less characterized. We uncover that upregulation of the AP-1 (activator protein-1) transcription factors, along with restored YAP (yes-associated protein) and TEAD activity, drives resistance to GNE-7883, a pan-TEAD inhibitor. Acute GNE-7883 treatment abrogates YAP-TEAD binding and attenuates FOSL1 (FOS like 1) activity. TEAD inhibitor resistant cells restore YAP and TEAD chromatin occupancy, acquire additional FOSL1 binding and exhibit increased MAPK (mitogen-activated protein kinase) pathway activity. FOSL1 is required for the chromatin binding of YAP and TEAD. This study describes a clinically relevant interplay between the Hippo and MAPK pathway and highlights the key role of MAPK pathway inhibitors in mitigating resistance to TEAD inhibition in Hippo pathway dependent cancers.

Date: 2025
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-025-56634-y Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56634-y

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-025-56634-y

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().