TY - JOUR AU - Rio-Vilariño, A. AU - Cenigaonandia-Campillo, A. AU - García-Bautista, A. AU - Mateos-Gómez, P.A. AU - Schlaepfer, M.I. AU - del Puerto-Nevado, L. AU - Aguilera, O. AU - García-García, L. AU - Galeano, C. AU - de Miguel, I. AU - Serrano-López, J. AU - Baños, N. AU - Fernández-Aceñero, M.J. AU - Lacal, J.C. AU - Medico, E. AU - García-Foncillas, J. AU - Cebrián, A. T1 - Inhibition of the AURKA/YAP1 axis is a promising therapeutic option for overcoming cetuximab resistance in colorectal cancer stem cells LA - eng PY - 2024/05/03/ SP - 1402 EP - 1413 T2 - British Journal of Cancer SN - 1532-1827 VL - 130 IS - 8 PB - Springer Nature AB - 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. (Figure presented.) DO - 10.1038/S41416-024-02649-Z UR - https://portalcientifico.uah.es/documentos/65ff9364abcd4f04a9706927 DP - Dialnet - Portal de la Investigación ER -