期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 115, 期 11, 页码 E2594-E2603出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1717820115
关键词
NOXA; apoptosis; HER2 amplification; targeted therapies; MCL-1 inhibitor
资金
- NIH-NCI Cancer Center Support Grant [P30 CA016059]
- NCI Career Development Award [K22 CA175276]
- Mary Kay Foundation [017-75]
- Breast Cancer Research Foundation [BCRF-17-008]
- Instituto de Salud Carlos III [PI16/00253]
- Spanish Association Against Cancer (AECC)
- Banco Bilbao Vizcaya Argentaria (BBVA) Foundation
- la Caixa Foundation
- Miguel Servet Program (ISCIII) [CP14/00228]
- NIH [P30CA008748]
- Breast Cancer Research Foundation
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 a (ESR1). Reduced ESR1 expression in turn prevents ER alpha-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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据