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- Title
Inhibition of the AURKA/YAP1 axis is a promising therapeutic option for overcoming cetuximab resistance in colorectal cancer stem cells.
- Authors
Rio-Vilariño, Anxo; Cenigaonandia-Campillo, Aiora; García-Bautista, Ana; Mateos-Gómez, Pedro A.; Schlaepfer, Marina I.; del Puerto-Nevado, Laura; Aguilera, Oscar; García-García, Laura; Galeano, Carlos; de Miguel, Irene; Serrano-López, Juana; Baños, Natalia; Fernández-Aceñero, María Jesús; Lacal, Juan Carlos; Medico, Enzo; García-Foncillas, Jesús; Cebrián, Arancha
- Abstract
Background: Primary resistance to anti-EGFR therapies affects 40% of metastatic colorectal cancer patients harbouring wild-type RAS/RAF. YAP1 activation is associated with this resistance, prompting an investigation into AURKA's role in mediating YAP1 phosphorylation at Ser397, as observed in breast cancer. Methods: We used transcriptomic analysis along with in vitro and in vivo models of RAS/RAF wild-type CRC to study YAP1 Ser397 phosphorylation as a potential biomarker for cetuximab resistance. We assessed cetuximab efficacy using CCK8 proliferation assays and cell cycle analysis. Additionally, we examined the effects of AURKA inhibition with alisertib and created a dominant-negative YAP1 Ser397 mutant to assess its impact on cancer stem cell features. Results: The RAS/RAF wild-type CRC models exhibiting primary resistance to cetuximab prominently displayed elevated YAP1 phosphorylation at Ser397 primarily mediated by AURKA. AURKA-induced YAP1 phosphorylation was identified as a key trigger for cancer stem cell reprogramming. Consequently, we found that AURKA inhibition had the capacity to effectively restore cetuximab sensitivity and concurrently suppress the cancer stem cell phenotype. Conclusions: AURKA inhibition holds promise as a therapeutic approach to overcome cetuximab resistance in RAS/RAF wild-type colorectal cancer, offering a potential means to counter the development of cancer stem cell phenotypes associated with cetuximab resistance.
- Publication
British Journal of Cancer, 2024, Vol 130, Issue 8, p1402
- ISSN
0007-0920
- Publication type
Article
- DOI
10.1038/s41416-024-02649-z