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EGFR and HER2 hyper-activation mediates resistance to endocrine therapy and CDK4/6 inhibitors in ER+ breast cancer.
Belli, Stefania; Esposito, Daniela; Ascione, Claudia M; Messina, Francesca; Napolitano, Fabiana; Servetto, Alberto; De Angelis, Carmine; Bianco, Roberto; Formisano, Luigi.
Afiliación
  • Belli S; Department of Clinical Medicine and Surgery, University of Naples "Federico II", 80131 Naples, Italy. Electronic address: stefania.bell21@gmail.com.
  • Esposito D; Department of Clinical Medicine and Surgery, University of Naples "Federico II", 80131 Naples, Italy. Electronic address: daniela.esposito1989@gmail.com.
  • Ascione CM; Department of Clinical Medicine and Surgery, University of Naples "Federico II", 80131 Naples, Italy. Electronic address: claudia97ascione@gmail.com.
  • Messina F; Department of Clinical Medicine and Surgery, University of Naples "Federico II", 80131 Naples, Italy. Electronic address: francescamessina507@gmail.com.
  • Napolitano F; Department of Clinical Medicine and Surgery, University of Naples "Federico II", 80131 Naples, Italy. Electronic address: fabi.napolitano@gmail.com.
  • Servetto A; Department of Clinical Medicine and Surgery, University of Naples "Federico II", 80131 Naples, Italy. Electronic address: alberto.servetto@unina.it.
  • De Angelis C; Department of Clinical Medicine and Surgery, University of Naples "Federico II", 80131 Naples, Italy. Electronic address: carmine.deangelis1@unina.it.
  • Bianco R; Department of Clinical Medicine and Surgery, University of Naples "Federico II", 80131 Naples, Italy. Electronic address: robianco@unina.it.
  • Formisano L; Department of Clinical Medicine and Surgery, University of Naples "Federico II", 80131 Naples, Italy. Electronic address: luigi.formisano1@unina.it.
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias de la Mama / Receptores de Estrógenos / Receptor ErbB-2 / Resistencia a Antineoplásicos / Quinasa 4 Dependiente de la Ciclina / Quinasa 6 Dependiente de la Ciclina / Receptores ErbB Idioma: En Revista: Cancer Lett Año: 2024 Tipo del documento: Article Pais de publicación: Irlanda

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias de la Mama / Receptores de Estrógenos / Receptor ErbB-2 / Resistencia a Antineoplásicos / Quinasa 4 Dependiente de la Ciclina / Quinasa 6 Dependiente de la Ciclina / Receptores ErbB Idioma: En Revista: Cancer Lett Año: 2024 Tipo del documento: Article Pais de publicación: Irlanda