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

TEAD transcription factors (TEAD1–4) are the main effectors of the Hippo signaling pathway and play a central role in the progression of various cancers. Although targeted therapies have shown initial effectiveness, resistance often emerges, and the mechanisms underlying resistance to TEAD inhibition remain poorly understood. In this study, we reveal that resistance to GNE-7883, a pan-TEAD inhibitor, is driven by the upregulation of activator protein-1 (AP-1) transcription factors, accompanied by restored activity of both YAP (Yes-associated protein) and TEAD.

Short-term treatment with GNE-7883 disrupts YAP-TEAD interactions and reduces the activity of FOSL1 (FOS-like 1), a key AP-1 component. However, in cells that develop resistance to the inhibitor, YAP and TEAD regain their ability to bind chromatin, and FOSL1 binding is enhanced. These resistant cells also display heightened activation of the MAPK (mitogen-activated protein kinase) pathway. Importantly, FOSL1 is found to be essential for the chromatin association of both YAP and TEAD, underscoring its pivotal role in the resistance mechanism.

This study uncovers a clinically relevant interaction between the Hippo and MAPK signaling pathways and emphasizes the importance of targeting the MAPK pathway to overcome resistance to TEAD inhibition in cancers that rely on Hippo pathway signaling.