Carfilzomib公司
癌症研究
平方毫米
蛋白酶体抑制剂
蛋白酶体
未折叠蛋白反应
综合应力响应
生物
细胞生物学
细胞凋亡
遗传学
翻译(生物学)
基因
信使核糖核酸
作者
Michael P. Ludwig,Matthew D. Galbraith,Neetha Paul Eduthan,Amanda A. Hill,Michael R. Clay,Cristiam Moreno Tellez,Breelyn A. Wilky,Anthony Elias,Joaquı́n M. Espinosa,Kelly D. Sullivan
出处
期刊:Cancer Research
[American Association for Cancer Research]
日期:2023-05-19
卷期号:83 (15): 2543-2556
被引量:2
标识
DOI:10.1158/0008-5472.can-22-3173
摘要
Abstract Liposarcoma is the most commonly occurring soft-tissue sarcoma and is frequently characterized by amplification of chromosome region 12q13–15 harboring the oncogenes MDM2 and CDK4. This unique genetic profile makes liposarcoma an attractive candidate for targeted therapeutics. While CDK4/6 inhibitors are currently employed for treatment of several cancers, MDM2 inhibitors have yet to attain clinical approval. Here, we report the molecular characterization of the response of liposarcoma to the MDM2 inhibitor nutlin-3. Treatment with nutlin-3 led to upregulation of two nodes of the proteostasis network: the ribosome and the proteasome. CRISPR/Cas9 was used to perform a genome-wide loss of function screen that identified PSMD9, which encodes a proteasome subunit, as a regulator of response to nutlin-3. Accordingly, pharmacologic studies with a panel of proteasome inhibitors revealed strong combinatorial induction of apoptosis with nutlin-3. Mechanistic studies identified activation of the ATF4/CHOP stress response axis as a potential node of interaction between nutlin-3 and the proteasome inhibitor carfilzomib. CRISPR/Cas9 gene editing experiments confirmed that ATF4, CHOP, and the BH3-only protein, NOXA, are all required for nutlin-3 and carfilzomib-induced apoptosis. Furthermore, activation of the unfolded protein response using tunicamycin and thapsigargin was sufficient to activate the ATF4/CHOP stress response axis and sensitize to nutlin-3. Finally, cell line and patient-derived xenograft models demonstrated combinatorial effects of treatment with idasanutlin and carfilzomib on liposarcoma growth in vivo. Together, these data indicate that targeting of the proteasome could improve the efficacy of MDM2 inhibitors in liposarcoma. Significance: Targeting the proteasome in combination with MDM2 inhibition activates the ATF4/CHOP stress response axis to induce apoptosis in liposarcoma, providing a potential therapeutic approach for the most common soft-tissue sarcoma.
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