Rio-Vilariño Anxo, Garcia-Bautista Ana, Cenigaonandia-Campillo Aiora, Mateos-Gomez Pedro A, Garcia-Garcia Laura, Schlaepfer Marina I, Garcia-Hernandez Laura, Puerto-Nevado Laura Del, Aguilera Oscar, Baños Natalia, Minguez Pablo, Castellano Víctor Manuel, Garcia-Foncillas Jesús, Cebrian Arancha
Translational Oncology Division, Oncohealth Institute, IIS - Fundación Jiménez Díaz University Hospital (IIS-FJD, UAM), Madrid, Spain.
Biochemistry and Molecular Biology Unit, Department of System Biology, School of Medicine and Health Sciences, University of Alcalá, Alcalá de Henares, Madrid, Spain.
Mol Ther Oncol. 2025 Aug 9;33(3):201032. doi: 10.1016/j.omton.2025.201032. eCollection 2025 Sep 18.
Anti-epidermal growth factor receptor (EGFR) therapies are the most recommended first-line treatment for 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 and 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.
根据欧洲医学肿瘤学会指南，抗表皮生长因子受体（EGFR）疗法是野生型不可切除转移性结直肠癌（CRC）最推荐的一线治疗方法。然而，原发性耐药使这种治疗对近40%的患者无效。我们之前的研究通过非经典的、不依赖于Hippo的Yes相关蛋白1（YAP1）激活，确定极光激酶A（AURKA）是关键的耐药驱动因素。然而，另一个主要的Hippo共激活因子，即具有PDZ结合基序的转录共激活因子（TAZ），在这种耐药机制中的作用仍未得到探索。通过将临床前模型（包括细胞系和患者来源的异种移植模型）与RNA测序相结合，我们研究了TAZ过表达对由AURKA/YAP1轴驱动的西妥昔单抗耐药性的影响。我们的研究结果表明，TAZ过表达维持YAP1介导的耐药性和干性。即使在YAP1受到抑制的情况下，过表达TAZ的细胞对抗EGFR疗法仍然无反应，而同时沉默YAP1/TAZ可恢复敏感性。使用III期AURKA抑制剂alisertib进行治疗，可同时使YAP1和TAZ不稳定，通过抑制干性恢复抗EGFR疗效。转录组分析进一步表明，抑制AURKA以及同时抑制YAP1/TAZ会破坏干细胞样特征，并揭示影响核苷酸代谢的转录失调。这些发现表明，AURKA协调YAP1/TAZ的相互作用，这对于驱动干性和对抗EGFR疗法的耐药性至关重要，突出了AURKA抑制剂作为一种有前景的策略，可增强转移性CRC的抗EGFR治疗效果。
