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MAPK4 促进三阴性乳腺癌生长并降低肿瘤对 PI3K 阻断的敏感性。

MAPK4 promotes triple negative breast cancer growth and reduces tumor sensitivity to PI3K blockade.

机构信息

Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.

Department of Medicine, Baylor College of Medicine, Houston, TX, USA.

出版信息

Nat Commun. 2022 Jan 11;13(1):245. doi: 10.1038/s41467-021-27921-1.

DOI:10.1038/s41467-021-27921-1
PMID:35017531
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8752662/
Abstract

About 15-20% of breast cancer (BCa) is triple-negative BCa (TNBC), a devastating disease with limited therapeutic options. Aberrations in the PI3K/PTEN signaling pathway are common in TNBC. However, the therapeutic impact of PI3K inhibitors in TNBC has been limited and the mechanism(s) underlying this lack of efficacy remain elusive. Here, we demonstrate that a large subset of TNBC expresses significant levels of MAPK4, and this expression is critical for driving AKT activation independent of PI3K and promoting TNBC cell and xenograft growth. The ability of MAPK4 to bypass PI3K for AKT activation potentially provides a direct mechanism regulating tumor sensitivity to PI3K inhibition. Accordingly, repressing MAPK4 greatly sensitizes TNBC cells and xenografts to PI3K blockade. Altogether, we conclude that high MAPK4 expression defines a large subset or subtype of TNBC responsive to MAPK4 blockage. Targeting MAPK4 in this subset/subtype of TNBC both represses growth and sensitizes tumors to PI3K blockade.

摘要

大约 15-20%的乳腺癌（BCa）是三阴性乳腺癌（TNBC），这是一种具有有限治疗选择的破坏性疾病。PI3K/PTEN 信号通路的异常在 TNBC 中很常见。然而，PI3K 抑制剂在 TNBC 中的治疗效果有限，其疗效缺失的机制仍不清楚。在这里，我们证明了一大类 TNBC 表达出显著水平的 MAPK4，这种表达对于驱动 AKT 激活是至关重要的，而这种激活是独立于 PI3K 发生的，并促进了 TNBC 细胞和异种移植物的生长。MAPK4 绕过 PI3K 激活 AKT 的能力可能提供了一个直接的机制来调节肿瘤对 PI3K 抑制的敏感性。因此，抑制 MAPK4 能极大地提高 TNBC 细胞和异种移植物对 PI3K 阻断的敏感性。总之，我们得出结论，高表达 MAPK4 定义了对 MAPK4 阻断有反应的一大类或亚类 TNBC。在这部分或亚类 TNBC 中靶向 MAPK4 既能抑制肿瘤生长，又能提高肿瘤对 PI3K 阻断的敏感性。

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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f68c/8752662/64424be5a291/41467_2021_27921_Fig8_HTML.jpg
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