Targeting Cholesterol Biosynthesis with Statins Synergizes with AKT Inhibitors in Triple-Negative Breast Cancer.

IF 12.5 1区 医学 Q1 ONCOLOGY
Alissandra L Hillis, Timothy D Martin, Haley E Manchester, Jenny Högström, Na Zhang, Emmalyn Lecky, Nina Kozlova, Jonah Lee, Nicole S Persky, David E Root, Myles Brown, Karen Cichowski, Stephen J Elledge, Taru Muranen, David A Fruman, Simon T Barry, John G Clohessy, Ralitsa R Madsen, Alex Toker
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Abstract

Triple-negative breast cancer (TNBC) is responsible for a disproportionate number of breast cancer patient deaths due to extensive molecular heterogeneity, high recurrence rates, and lack of targeted therapies. Dysregulation of the phosphoinositide 3-kinase (PI3K)/AKT pathway occurs in approximately 50% of TNBC patients. Here, we performed a genome-wide CRISPR/Cas9 screen with PI3Kα and AKT inhibitors to find targetable synthetic lethalities in TNBC. Cholesterol homeostasis was identified as a collateral vulnerability with AKT inhibition. Disruption of cholesterol homeostasis with pitavastatin synergized with AKT inhibition to induce TNBC cytotoxicity in vitro in mouse TNBC xenografts and in patient-derived estrogen receptor (ER)-negative breast cancer organoids. Neither ER-positive breast cancer cell lines nor ER-positive organoids were sensitive to combined AKT inhibitor and pitavastatin. Mechanistically, TNBC cells showed impaired sterol regulatory element-binding protein 2 (SREBP-2) activation in response to single-agent or combination treatment with AKT inhibitor and pitavastatin, which was rescued by inhibition of the cholesterol-trafficking protein Niemann-Pick C1 (NPC1). NPC1 loss caused lysosomal cholesterol accumulation, decreased endoplasmic reticulum cholesterol levels, and promoted SREBP-2 activation. Taken together, these data identify a TNBC-specific vulnerability to the combination of AKT inhibitors and pitavastatin mediated by dysregulated cholesterol trafficking. These findings support combining AKT inhibitors with pitavastatin as a therapeutic modality in TNBC. Significance: Two FDA-approved compounds, AKT inhibitors and pitavastatin, synergize to induce cell death in triple-negative breast cancer, motivating evaluation of the efficacy of this combination in clinical trials.

用他汀类药物靶向胆固醇合成与 AKT 抑制剂协同治疗三阴性乳腺癌
由于广泛的分子异质性、高复发率和缺乏靶向疗法,三阴性乳腺癌(TNBC)造成了过多的乳腺癌患者死亡。约50%的TNBC患者会出现磷酸肌酸3-激酶(PI3K)/AKT通路失调。在这里,我们用PI3Kα和AKT抑制剂进行了一次全基因组CRISPR/Cas9筛选,以寻找TNBC中可靶向的合成致死因子。胆固醇稳态被认为是AKT抑制的附带弱点。用匹伐他汀破坏胆固醇稳态与 AKT 抑制协同作用,可在体外、小鼠 TNBC 异种移植和源自患者的雌激素受体(ER)阴性乳腺癌器官组织中诱导 TNBC 细胞毒性。ER阳性乳腺癌细胞系和ER阳性有机体对AKT抑制剂和匹伐他汀的联合作用都不敏感。从机理上讲,TNBC细胞对AKT抑制剂和匹伐他汀的单药或联合治疗表现出固醇调节元件结合蛋白2(SREBP-2)激活受损的反应,而抑制胆固醇转运蛋白Niemann-Pick C1(NPC1)则可挽救这种反应。NPC1 缺失会导致溶酶体胆固醇积累、内质网胆固醇水平下降并促进 SREBP-2 的活化。综上所述,这些数据确定了TNBC对AKT抑制剂和匹伐他汀联合治疗的特异性易感性,这种易感性是由胆固醇运输失调介导的。这些发现支持将AKT抑制剂与匹伐他汀联合作为TNBC的一种治疗方法。.
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来源期刊
Cancer research
Cancer research 医学-肿瘤学
CiteScore
16.10
自引率
0.90%
发文量
7677
审稿时长
2.5 months
期刊介绍: Cancer Research, published by the American Association for Cancer Research (AACR), is a journal that focuses on impactful original studies, reviews, and opinion pieces relevant to the broad cancer research community. Manuscripts that present conceptual or technological advances leading to insights into cancer biology are particularly sought after. The journal also places emphasis on convergence science, which involves bridging multiple distinct areas of cancer research. With primary subsections including Cancer Biology, Cancer Immunology, Cancer Metabolism and Molecular Mechanisms, Translational Cancer Biology, Cancer Landscapes, and Convergence Science, Cancer Research has a comprehensive scope. It is published twice a month and has one volume per year, with a print ISSN of 0008-5472 and an online ISSN of 1538-7445. Cancer Research is abstracted and/or indexed in various databases and platforms, including BIOSIS Previews (R) Database, MEDLINE, Current Contents/Life Sciences, Current Contents/Clinical Medicine, Science Citation Index, Scopus, and Web of Science.
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