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

Author

Listed:
  • 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
    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
    Genentech Inc)

  • Matthew Grimmer

    (Genentech Inc
    Genentech Inc)

  • Shiqi Xie

    (Genentech Inc)

  • Bence Daniel

    (Genentech Inc)

  • Xiaosai Yao

    (Genentech Inc
    Genentech Inc)

  • Anwesha Dey

    (Genentech Inc)

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.

Suggested Citation

  • 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 & Jani, 2025. "Cooperation between the Hippo and MAPK pathway activation drives acquired resistance to TEAD inhibition," Nature Communications, Nature, vol. 16(1), pages 1-21, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56634-y
    DOI: 10.1038/s41467-025-56634-y
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