Inhibition of the AURKA/YAP1 axis is a promising therapeutic option for overcoming cetuximab resistance in colorectal cancer stem cells PMID: 38467828

ADC Targets in Oncology

2026-04-10

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

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. [email protected].
12. Translational Oncology Division, Oncohealth Institute, Instituto de Investigación Sanitaria Fundación Jiménez Díaz, Fundación Jiménez University Hospital (IIS-FJD, UAM), Madrid, Spain. [email protected].

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.