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Cooperation between the Hippo and MAPK pathway activation drives acquired resistance to TEAD inhibition
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Cooperation between the Hippo and MAPK pathway activation drives acquired resistance to TEAD inhibition
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Journal Article
Cooperation between the Hippo and MAPK pathway activation drives acquired resistance to TEAD inhibition
2025
Overview
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.
The underlying mechanism of acquired resistance to targeted therapy in cancer remains to be explored. Here, the authors show that upregulation of the FOSL1 transcription factor restores YAP/TEAD occupancy on chromatin to drive resistance to GNE-7883, an allosteric TEAD inhibitor.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 13/89
/ 38
/ 45/15
/ 45/91
/ 631/154
/ 631/67
/ Adaptor Proteins, Signal Transducing - genetics
/ Adaptor Proteins, Signal Transducing - metabolism
/ Animals
/ Binding
/ Cancer
/ DNA-Binding Proteins - antagonists & inhibitors
/ DNA-Binding Proteins - genetics
/ DNA-Binding Proteins - metabolism
/ Drug Resistance, Neoplasm - drug effects
/ Drug Resistance, Neoplasm - genetics
/ Humanities and Social Sciences
/ Humans
/ Kinases
/ MAP Kinase Signaling System - drug effects
/ Mice
/ Protein Serine-Threonine Kinases - genetics
/ Protein Serine-Threonine Kinases - metabolism
/ Proteins
/ Proto-Oncogene Proteins c-fos
/ Science
/ TEA Domain Transcription Factors
/ Transcription Factors - antagonists & inhibitors
/ Transcription Factors - genetics
