Coamplification of miR-4728 protects HER2 -amplified breast cancers from targeted therapy
Floros, Konstantinos V. (Philips Institute for Oral Health Research)
Lochmann, Timothy L. (Philips Institute for Oral Health Research)
Hu, Bin (Virginia Commonwealth University School of Medicine)
Monterrubio, Carles (Memorial Sloan Kettering Cancer Center)
Hughes, Mark T. (Philips Institute for Oral Health Research)
Wells, Jason D. (Norris Cotton Cancer Center)
Bernadó Morales, Cristina (Vall d'Hebron Institut d'Oncologia)
Ghotra, Maninderjit S. (Philips Institute for Oral Health Research)
Costa, Carlotta (Massachusetts General Hospital (Boston))
Souers, Andrew J. (AbbVie Inc)
Boikos, Sosipatros A. (Virginia Commonwealth University)
Leverson, Joel D. (AbbVie Inc)
Tan, Ming (University of South Alabama)
Serra, Violeta (Vall d'Hebron Institut d'Oncologia)
Koblinski, Jennifer E. (Virginia Commonwealth University School of Medicine)
Arribas, Joaquín V (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Prat, Aleix (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Paré Brunet, Laia (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Miller, Todd W. (Norris Cotton Cancer Center)
Dozmorov, Mikhail G. (Virginia Commonwealth University)
Harada, Hisashi (Philips Institute for Oral Health Research)
Windle, Brad E. (Philips Institute for Oral Health Research)
Scaltriti, Maurizio (Memorial Sloan Kettering Cancer Center)
Faber, Anthony C. (Philips Institute for Oral Health Research)

Fecha:	2018
Resumen:	In HER2 -amplified breast cancers, HER2 inhibitors have been very successful as adjuvant therapy but not as monotherapy. Here, we demonstrate that coamplification of a HER2 intronic miRNA causes intrinsic resistance to HER2 inhibitors by indirectly down-regulating the pro-apoptotic NOXA. Importantly, coinhibition with MCL-1 inhibitors overcomes this resistance. HER2 (ERBB2) amplification is a driving oncogenic event in breast cancer. Clinical trials have consistently shown the benefit of HER2 inhibitors (HER2i) in treating patients with both local and advanced HER2+ breast cancer. Despite this benefit, their efficacy as single agents is limited, unlike the robust responses to other receptor tyrosine kinase inhibitors like EGFR inhibitors in EGFR -mutant lung cancer. Interestingly, the lack of HER2i efficacy occurs despite sufficient intracellular signaling shutdown following HER2i treatment. Exploring possible intrinsic causes for this lack of response, we uncovered remarkably depressed levels of NOXA, an endogenous inhibitor of the antiapoptotic MCL-1, in HER2 -amplified breast cancer. Upon investigation of the mechanism leading to low NOXA, we identified a micro-RNA encoded in an intron of HER2, termed miR-4728, that targets the mRNA of the Estrogen Receptor α (ESR1). Reduced ESR1 expression in turn prevents ERα-mediated transcription of NOXA, mitigating apoptosis following treatment with the HER2i lapatinib. Importantly, resistance can be overcome with pharmacological inhibition of MCL-1. More generally, while many cancers like EGFR -mutant lung cancer are driven by activated kinases that when drugged lead to robust monotherapeutic responses, we demonstrate that the efficacy of targeted therapies directed against oncogenes active through focal amplification may be mitigated by coamplified genes.
Ayudas:	Instituto de Salud Carlos III PI16-00253 Instituto de Salud Carlos III P14-00228
Derechos:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió publicada
Materia:	NOXA ; Apoptosis ; HER2 amplification ; Targeted therapies ; MCL-1 inhibitor
Publicado en:	Proceedings of the National Academy of Sciences of the United States of America, Vol. 115 (february 2018) , p. E2594-E2603, ISSN 1091-6490

DOI: 10.1073/pnas.1717820115
PMID: 29476008

10 p, 1.3 MB

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