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MYC 是乳腺癌中 mTOR 抑制剂耐药的一个具有临床意义的驱动因素。

MYC is a clinically significant driver of mTOR inhibitor resistance in breast cancer.

机构信息

Division of Molecular Carcinogenesis, Netherlands Cancer Institute, Amsterdam, Netherlands.

Division of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, Netherlands.

出版信息

J Exp Med. 2023 Nov 6;220(11). doi: 10.1084/jem.20211743. Epub 2023 Aug 29.

DOI:10.1084/jem.20211743
PMID:37642941
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10465700/
Abstract

Targeting the PI3K-AKT-mTOR pathway is a promising therapeutic strategy for breast cancer treatment. However, low response rates and development of resistance to PI3K-AKT-mTOR inhibitors remain major clinical challenges. Here, we show that MYC activation drives resistance to mTOR inhibitors (mTORi) in breast cancer. Multiomic profiling of mouse invasive lobular carcinoma (ILC) tumors revealed recurrent Myc amplifications in tumors that acquired resistance to the mTORi AZD8055. MYC activation was associated with biological processes linked to mTORi response and counteracted mTORi-induced translation inhibition by promoting translation of ribosomal proteins. In vitro and in vivo induction of MYC conferred mTORi resistance in mouse and human breast cancer models. Conversely, AZD8055-resistant ILC cells depended on MYC, as demonstrated by the synergistic effects of mTORi and MYCi combination treatment. Notably, MYC status was significantly associated with poor response to everolimus therapy in metastatic breast cancer patients. Thus, MYC is a clinically relevant driver of mTORi resistance that may stratify breast cancer patients for mTOR-targeted therapies.

摘要

针对 PI3K-AKT-mTOR 通路的治疗是乳腺癌治疗的一种有前途的治疗策略。然而，PI3K-AKT-mTOR 抑制剂的低反应率和耐药性的发展仍然是主要的临床挑战。在这里，我们表明 MYC 的激活导致乳腺癌对 mTOR 抑制剂（mTORi）产生耐药性。对小鼠浸润性小叶癌（ILC）肿瘤的多组学分析显示，在对 mTORi AZD8055 产生耐药性的肿瘤中，Myc 扩增是复发性的。MYC 的激活与与 mTORi 反应相关的生物学过程有关，并通过促进核糖体蛋白的翻译来抵消 mTORi 诱导的翻译抑制。在体外和体内诱导 MYC 赋予了小鼠和人类乳腺癌模型对 mTORi 的耐药性。相反，AZD8055 耐药性的 ILC 细胞依赖于 MYC，如 mTORi 和 MYCi 联合治疗的协同作用所证明的那样。值得注意的是，MYC 状态与转移性乳腺癌患者对依维莫司治疗的反应不良显著相关。因此，MYC 是 mTORi 耐药性的一个临床相关驱动因素，可能对接受 mTOR 靶向治疗的乳腺癌患者进行分层。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28f4/10465700/726174c47c05/JEM_20211743_Fig9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28f4/10465700/37ae5c5f0b6d/JEM_20211743_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28f4/10465700/ca8b12ba8dec/JEM_20211743_FigS1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28f4/10465700/2f87571cb0c5/JEM_20211743_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28f4/10465700/4f465895e2b5/JEM_20211743_FigS2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28f4/10465700/6cdfd2284e68/JEM_20211743_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28f4/10465700/2f3c85183232/JEM_20211743_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28f4/10465700/82833183b56b/JEM_20211743_FigS3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28f4/10465700/bcb09995a187/JEM_20211743_Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28f4/10465700/09bcbd268630/JEM_20211743_FigS4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28f4/10465700/fa5fed5f988b/JEM_20211743_Fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28f4/10465700/3fd4d6d00c87/JEM_20211743_Fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28f4/10465700/ed6b1c90609c/JEM_20211743_FigS5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28f4/10465700/d6b09ea88cae/JEM_20211743_Fig8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28f4/10465700/726174c47c05/JEM_20211743_Fig9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28f4/10465700/37ae5c5f0b6d/JEM_20211743_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28f4/10465700/ca8b12ba8dec/JEM_20211743_FigS1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28f4/10465700/2f87571cb0c5/JEM_20211743_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28f4/10465700/4f465895e2b5/JEM_20211743_FigS2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28f4/10465700/6cdfd2284e68/JEM_20211743_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28f4/10465700/2f3c85183232/JEM_20211743_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28f4/10465700/82833183b56b/JEM_20211743_FigS3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28f4/10465700/bcb09995a187/JEM_20211743_Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28f4/10465700/09bcbd268630/JEM_20211743_FigS4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28f4/10465700/fa5fed5f988b/JEM_20211743_Fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28f4/10465700/3fd4d6d00c87/JEM_20211743_Fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28f4/10465700/ed6b1c90609c/JEM_20211743_FigS5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28f4/10465700/d6b09ea88cae/JEM_20211743_Fig8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28f4/10465700/726174c47c05/JEM_20211743_Fig9.jpg

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