@article{20.500.12766/808,
year = {2025},
month = {9},
url = {https://hdl.handle.net/20.500.12766/808},
abstract = {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.},
publisher = {Elsevier Inc.},
title = {Aurora kinase A drives non-canonical YAP1/TAZ crosstalk to sustain primary resistance to anti-EGFR therapies in colorectal cancer},
doi = {10.1016/j.omton.2025.201032},
journal = {Molecular Therapy: Oncology},
keywords = {Anti-EGFR},
keywords = {Aurora kinase A},
keywords = {Cancer stem cells},
keywords = {Cetuximab},
keywords = {Drug resistance},
keywords = {Metastatic colorectal cancer},
keywords = {Non-canonical Hippo pathway},
keywords = {TAZ},
keywords = {YAP1},
volume = {33},
author = {Rio-Vilariño, Anxo and Garcia-Bautista, Ana and Cenigaonandia-Campillo, Aiora and Mateos-Gomez, Pedro A. and Garcia-Garcia, Laura and Schlaepfer, Marina I. and Garcia-Hernandez, Laura and Puerto-Nevado, Laura del and Aguilera, Oscar and Baños, Natalia and Minguez, Pablo and Castellano, Víctor Manuel and García-Foncillas, Jesús and Cebrian, Arancha},
}