Coamplification of miR-4728 protects HER2 -amplified breast cancers from targeted therapy

Proceedings of the National Academy of Sciences of the United States of America
Konstantinos V FlorosAnthony C Faber

Abstract

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 ...Continue Reading

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Citations

Sep 27, 2018·Molecular & Cellular Oncology·Konstantinos V Floros, Anthony C Faber
Nov 16, 2019·Nature Communications·Joan MonteroRizwan Haq
Mar 20, 2020·Molecular Cancer·Francesca CrudeleStefano Volinia
Jun 19, 2019·BMC Genomics·Rolf SøkildeCarlos Rovira
Aug 9, 2018·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Kyung-A SongAnthony C Faber
Jan 9, 2021·International Journal of Genomics·Javad BehrooziHabibollah Mahmoodzadeh
Feb 17, 2021·Cell Death & Disease·Konstantinos V FlorosAnthony C Faber
Nov 18, 2020·Biochemistry. Biokhimii︠a︡·A A DaksN A Barlev
Apr 23, 2021·Journal of Hematology & Oncology·Haolan WangYongheng Chen
Jun 3, 2021·Cancers·Carter K FairchildSosipatros A Boikos

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Methods Mentioned

BETA
transfection
immunoprecipitation
FACS
xenografts
xenograft

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