Title |
Coamplification of miR-4728 protects HER2-amplified breast cancers from targeted therapy
|
---|---|
Published in |
Proceedings of the National Academy of Sciences of the United States of America, February 2018
|
DOI | 10.1073/pnas.1717820115 |
Pubmed ID | |
Authors |
Konstantinos V. Floros, Timothy L. Lochmann, Bin Hu, Carles Monterrubio, Mark T. Hughes, Jason D. Wells, Cristina Bernadó Morales, Maninderjit S. Ghotra, Carlotta Costa, Andrew J. Souers, Sosipatros A. Boikos, Joel D. Leverson, Ming Tan, Violeta Serra, Jennifer E. Koblinski, Joaquin Arribas, Aleix Prat, Laia Paré, Todd W. Miller, Mikhail G. Dozmorov, Hisashi Harada, Brad E. Windle, Maurizio Scaltriti, Anthony 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 inEGFR-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, inHER2-amplified breast cancer. Upon investigation of the mechanism leading to low NOXA, we identified a micro-RNA encoded in an intron ofHER2, termedmiR-4728, that targets the mRNA of the Estrogen Receptor α (ESR1). Reduced ESR1 expression in turn prevents ERα-mediated transcription ofNOXA, mitigating apoptosis following treatment with the HER2i lapatinib. Importantly, resistance can be overcome with pharmacological inhibition of MCL-1. More generally, while many cancers likeEGFR-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. |
X Demographics
Geographical breakdown
Country | Count | As % |
---|---|---|
Spain | 10 | 56% |
France | 1 | 6% |
United States | 1 | 6% |
Italy | 1 | 6% |
India | 1 | 6% |
Unknown | 4 | 22% |
Demographic breakdown
Type | Count | As % |
---|---|---|
Members of the public | 10 | 56% |
Scientists | 4 | 22% |
Practitioners (doctors, other healthcare professionals) | 3 | 17% |
Science communicators (journalists, bloggers, editors) | 1 | 6% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
Unknown | 58 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Researcher | 10 | 17% |
Student > Ph. D. Student | 7 | 12% |
Student > Bachelor | 6 | 10% |
Student > Postgraduate | 5 | 9% |
Student > Master | 5 | 9% |
Other | 9 | 16% |
Unknown | 16 | 28% |
Readers by discipline | Count | As % |
---|---|---|
Medicine and Dentistry | 15 | 26% |
Biochemistry, Genetics and Molecular Biology | 12 | 21% |
Agricultural and Biological Sciences | 8 | 14% |
Pharmacology, Toxicology and Pharmaceutical Science | 3 | 5% |
Psychology | 2 | 3% |
Other | 4 | 7% |
Unknown | 14 | 24% |