2. Academic Validation
  3. Inhibition of the AURKA/YAP1 axis is a promising therapeutic option for overcoming cetuximab resistance in colorectal cancer stem cells

Inhibition of the AURKA/YAP1 axis is a promising therapeutic option for overcoming cetuximab resistance in colorectal cancer stem cells

  • Br J Cancer. 2024 Mar 11. doi: 10.1038/s41416-024-02649-z.
Anxo Rio-Vilariño 1,  Aiora Cenigaonandia-Campillo 1,  Ana García-Bautista 1,  Pedro A Mateos-Gómez 2,  Marina I Schlaepfer 1,  Laura Del Puerto-Nevado 1,  Oscar Aguilera 1,  Laura García-García 1,  Carlos Galeano 3,  Irene de Miguel 2,  Juana Serrano-López 4,  Natalia Baños 5,  María Jesús Fernández-Aceñero 6,  Juan Carlos Lacal 7 8,  Enzo Medico 9 10,  Jesús García-Foncillas 11,  Arancha Cebrián 12
Affiliations

Affiliations

  • 1 Translational Oncology Division, Oncohealth Institute, Instituto de Investigación Sanitaria Fundación Jiménez Díaz, Fundación Jiménez University Hospital (IIS-FJD, UAM), Madrid, Spain.
  • 2 Biochemistry and Molecular Biology Unit, Department of System Biology, School of Medicine and Health Sciences, University of Alcalá. Alcalá de Henares, Madrid, Spain.
  • 3 Pathology Department, IIS-Fundación Jiménez Diaz-UAM, Madrid, Spain.
  • 4 Experimental Hematology Lab, IIS-Fundación Jimenez Díaz, UAM, Madrid, Spain.
  • 5 Preclinical program START Madrid-FJD, Hospital Fundación Jiménez Díaz-UAM, Madrid, Spain.
  • 6 Department of Pathology, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain.
  • 7 Instituto de Investigaciones Biomédicas, CSIC/UAM, Madrid, Spain.
  • 8 Instituto de Investigación Sanitaria Hospital La Paz, IDIPAZ, Madrid, Spain.
  • 9 Department of Oncology, Università degli Studi di Torino, Candiolo (TO), Italy.
  • 10 Candiolo Cancer Institute, FPO-IRCCS, Candiolo (TO), Italy.
  • 11 Translational Oncology Division, Oncohealth Institute, Instituto de Investigación Sanitaria Fundación Jiménez Díaz, Fundación Jiménez University Hospital (IIS-FJD, UAM), Madrid, Spain. jgfoncillas@fjd.es.
  • 12 Translational Oncology Division, Oncohealth Institute, Instituto de Investigación Sanitaria Fundación Jiménez Díaz, Fundación Jiménez University Hospital (IIS-FJD, UAM), Madrid, Spain. arancha.cebrian@quironsalud.es.
PMID: 38467828 DOI: 10.1038/s41416-024-02649-z
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.

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