Targeting transcription of MCL-1 sensitizes HER2-amplified breast cancers to HER2 inhibitors.
Cell Death Dis
; 12(2): 179, 2021 02 15.
Article
en En
| MEDLINE
| ID: mdl-33589591
ABSTRACT
Human epidermal growth factor receptor 2 gene (HER2) is focally amplified in approximately 20% of breast cancers. HER2 inhibitors alone are not effective, and sensitizing agents will be necessary to move away from a reliance on heavily toxic chemotherapeutics. We recently demonstrated that the efficacy of HER2 inhibitors is mitigated by uniformly low levels of the myeloid cell leukemia 1 (MCL-1) endogenous inhibitor, NOXA. Emerging clinical data have demonstrated that clinically advanced cyclin-dependent kinase (CDK) inhibitors are effective MCL-1 inhibitors in patients, and, importantly, well tolerated. We, therefore, tested whether the CDK inhibitor, dinaciclib, could block MCL-1 in preclinical HER2-amplified breast cancer models and therefore sensitize these cancers to dual HER2/EGFR inhibitors neratinib and lapatinib, as well as to the novel selective HER2 inhibitor tucatinib. Indeed, we found dinaciclib suppresses MCL-1 RNA and is highly effective at sensitizing HER2 inhibitors both in vitro and in vivo. This combination was tolerable in vivo. Mechanistically, liberating the effector BCL-2 protein, BAK, from MCL-1 results in robust apoptosis. Thus, clinically advanced CDK inhibitors may effectively combine with HER2 inhibitors and present a chemotherapy-free therapeutic strategy in HER2-amplified breast cancer, which can be tested immediately in the clinic.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Compuestos de Piridinio
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Neoplasias de la Mama
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Protocolos de Quimioterapia Combinada Antineoplásica
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Receptor ErbB-2
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Óxidos N-Cíclicos
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Inhibidores de Proteínas Quinasas
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Proteína 1 de la Secuencia de Leucemia de Células Mieloides
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Indolizinas
Tipo de estudio:
Clinical_trials
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Prognostic_studies
Límite:
Animals
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Female
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Humans
Idioma:
En
Revista:
Cell Death Dis
Año:
2021
Tipo del documento:
Article
País de afiliación:
Estados Unidos