小柯机器人

美国德州大学安德森癌症中心Rugang Zhang课题组发现，靶向甲羟戊酸途径通过促进焦亡抑制ARID1A失活的癌症。该项研究成果发表在2023年3月23日出版的《癌细胞》上。

他们证明了甲羟戊酸途径的抑制与免疫检查点封锁(ICB)协同作用，通过在ARID1A失活的透明细胞卵巢癌(OCCC)中驱动炎症小体调节的免疫调节焦亡。SWI/SNF失活下调了甲羟酸盐途径中的限速酶，如HMGCR和HMGCS1，这在ARID1A失活细胞中产生了对途径剩余活性的依赖。甲羟戊酸途径抑制剂如辛伐他汀抑制ARID1A突变体的生长，但不影响野生型OCCC。

此外，辛伐他汀与抗PD-L1抗体协同作用于由条件Arid1a失活驱动的遗传OCCC小鼠模型，和人源的具有免疫功能的Arid1a突变患者来源的OCCC小鼠模型。他们的数据表明，抑制甲羟戊酸途径同时抑制肿瘤细胞生长，并通过促进焦亡来增强抗肿瘤免疫，这与ICB协同抑制ARID1A突变的癌症。

据悉，ARID1A编码SWI/SNF复合物的一个亚基，在约50%的OCCC病例中发生突变。

附：英文原文

Title: Targeting the mevalonate pathway suppresses ARID1A-inactivated cancers by promoting pyroptosis

Author: Wei Zhou, Heng Liu, Zhe Yuan, Joseph Zundell, Martina Towers, Jianhuang Lin, Simona Lombardi, Hao Nie, Brennah Murphy, Tyler Yang, Chen Wang, Liping Liao, Aaron R. Goldman, Toshitha Kannan, Andrew V. Kossenkov, Ronny Drapkin, Luis J. Montaner, Daniel T. Claiborne, Nan Zhang, Shuai Wu, Rugang Zhang

Issue&Volume: 2023-03-23

Abstract: ARID1A, encoding a subunit of the SWI/SNF complex, is mutated in ～50% of clear cell ovariancarcinoma (OCCC) cases. Here we show that inhibition of the mevalonate pathway synergizeswith immune checkpoint blockade (ICB) by driving inflammasome-regulated immunomodulatingpyroptosis in ARID1A-inactivated OCCCs. SWI/SNF inactivation downregulates the rate-limiting enzymes inthe mevalonate pathway such as HMGCR and HMGCS1, which creates a dependence on theresidual activity of the pathway in ARID1A-inactivated cells. Inhibitors of the mevalonate pathway such as simvastatin suppressesthe growth of ARID1A mutant, but not wild-type, OCCCs. In addition, simvastatin synergizes with anti-PD-L1antibody in a genetic OCCC mouse model driven by conditional Arid1a inactivation and in a humanized immunocompetent ARID1A mutant patient-derived OCCC mouse model. Our data indicate that inhibition of themevalonate pathway simultaneously suppresses tumor cell growth and boosts antitumorimmunity by promoting pyroptosis, which synergizes with ICB in suppressing ARID1A-mutated cancers.

DOI: 10.1016/j.ccell.2023.03.002

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(23)00050-8

Cancer Cell：《癌细胞》，创刊于2002年。隶属于细胞出版社，最新IF：38.585
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