EGFR and HER2 hyper-activation mediates resistance to endocrine therapy and CDK4/6 inhibitors in ER+ breast cancer.
Cancer Lett
; 593: 216968, 2024 Jul 01.
Article
en En
| MEDLINE
| ID: mdl-38788968
ABSTRACT
In patients with ER + metastatic breast cancer (mBC), the first-line treatment involves the combination of endocrine therapy (ET) and CDK4/6 inhibitors (CDK4/6i). However, a significant group of patients experiences disease progression, emphasizing the urgent clinical need to identify novel anti-tumor therapies. We previously generated breast cancer cells resistant to the combination of fulvestrant (ER downregulator) and abemaciclib (CDK4/6 inhibitor) from MCF7 and T47D (MCF7-FAR and T47D-FAR). RNA-seq-based Gene Set Enrichment Analysis (GSEA) revealed hyper-activation of EGFR, HER2, and AKT signaling in both MCF7-FAR and T47D-FAR. Modulating EGFR or ERBB2 expression through loss- and gain-of-function experiments altered tumor sensitivity to fulvestrant and abemaciclib in parental and FAR spheroids, affecting ERK and AKT/S6 pathways. Cetuximab treatment overcame tumor resistance to fulvestrant and abemaciclib in FAR and EGFR-overexpressing breast cancer spheroids and xenografts. Likewise, patient-derived organoids (PDOs) from individuals with ER + mBC, progressing on palbociclib, exhibited up-regulation of EGFR and HER2 pathways. In conclusion, our findings suggest that inhibiting EGFR and HER2 pathways might overcome resistance to ET + CDK4/6i in selected patients with ER + mBC.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Neoplasias de la Mama
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Receptores de Estrógenos
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Receptor ErbB-2
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Resistencia a Antineoplásicos
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Quinasa 4 Dependiente de la Ciclina
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Quinasa 6 Dependiente de la Ciclina
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Receptores ErbB
Idioma:
En
Revista:
Cancer Lett
Año:
2024
Tipo del documento:
Article
Pais de publicación:
Irlanda