TY - JOUR AU - Rio-Vilariño,A. AU - Garcia-Bautista,A. AU - Cenigaonandia-Campillo,A. AU - Mateos-Gomez,P.A. AU - Garcia-Garcia,L. AU - Schlaepfer,M.I. AU - Garcia-Hernandez,L. AU - Puerto-Nevado,L.D. AU - Aguilera,O. AU - Baños,N. AU - Minguez,P. AU - Castellano,V.M. AU - Garcia-Foncillas,J. AU - Cebrian,A. KW - anti-EGFR KW - Aurora kinase A KW - cancer stem cells KW - cetuximab KW - drug resistance KW - metastatic colorectal cancer KW - non-canonical Hippo pathway KW - TAZ KW - YAP1 T1 - Aurora kinase A drives non-canonical YAP1/TAZ crosstalk to sustain primary resistance to anti-EGFR therapies in colorectal cancer LA - eng PY - 2025/09/18/ T2 - Molecular Therapy Oncology SN - 2950-3299 VL - 33 IS - 3 PB - Cell Press AB - Anti-epidermal growth factor receptor (EGFR) therapies are the most recommended first-line treatment for RAS/RAF wild-type unresectable metastatic colorectal cancer (CRC) according to the European Society for Medical Oncology guidelines. However, primary resistance renders this treatment ineffective for almost 40% of patients. Our previous work identified Aurora kinase A (AURKA) as a key resistance driver through non-canonical, Hippo-independent Yes-associated protein 1 (YAP1) activation. However, the role of the other main Hippo coactivator, transcriptional coactivator with PDZ-binding motif (TAZ), in this resistance mechanism remains unexplored. By integrating preclinical in vitro and in vivo models, including cell lines and patient-derived xenografts, with RNA sequencing, we investigated the impact of TAZ overexpression in cetuximab resistance driven by the AURKA/YAP1 axis. Our findings reveal that TAZ overexpression sustains YAP1-mediated resistance and stemness. Even under YAP1 suppression, TAZ-overexpressing cells remain unresponsive to anti-EGFR therapies, whereas dual YAP1/TAZ silencing restores sensitivity. Treatment with alisertib, a phase III AURKA inhibitor, simultaneously destabilizes YAP1 and TAZ, restoring anti-EGFR efficacy by suppressing stemness. Transcriptomic analyses further show that AURKA inhibition and dual YAP1/TAZ suppression disrupt stem-like traits and reveal transcriptional deregulations affecting nucleotide metabolism. These findings demonstrate that AURKA orchestrates YAP1/TAZ crosstalk, which is crucial for driving stemness and resistance to anti-EGFR therapies, highlighting AURKA inhibitors as a promising strategy to enhance anti-EGFR therapies in metastatic CRC. DO - 10.1016/J.OMTON.2025.201032 UR - https://portalcientifico.uah.es/documentos/68bc43d27a2d433de95160cd DP - Dialnet - Portal de la Investigación ER -