Enhanced Efficacy of Aurora Kinase Inhibitors in G2/M Checkpoint Deficient TP53 Mutant Uterine Carcinomas Is Linked to the Summation of LKB1-AKT-p53 Interactions.
Enhanced Efficacy of Aurora Kinase Inhibitors in G2/M Checkpoint Deficient TP53 Mutant Uterine Carcinomas Is Linked to the Summation of LKB1-AKT-p53 Interactions.
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DOI：
10.3390/cancers13092195
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发表时间：
2021-05-03
期刊：
影响因子：
5.2
通讯作者：
Hill SJ
中科院分区：
文献类型：
--
作者：
Lynch KN;Liu JF;Kesten N;Chow KH;Shetty A;He R;Afreen MF;Yuan L;Matulonis UA;Growdon WB;Muto MG;Horowitz NS;Feltmate CM;Worley MJ Jr;Berkowitz RS;Crum CP;Rueda BR;Hill SJ
子宫内膜癌是美国最常见的妇科恶性肿瘤。一旦子宫内膜癌逃离子宫并在远处生长，治疗选择有限。最具侵袭性和致命性的子宫内膜癌携带p53蛋白的改变，p53蛋白是许多细胞功能的关键监护人。这些p53改变在子宫内膜癌中的作用尚不清楚。这项工作的目的是使用p53改变的子宫内膜癌模型来了解这些p53改变可能赋予子宫内膜癌哪些（如果有的话）治疗靶向脆弱性。在这里，我们表明，许多这些p53改变的细胞有细胞分裂的问题，可以与新的单一和组合疗法的目标。这些发现可能会为难以治疗的晚期子宫内膜癌带来相关的新疗法。子宫癌（UC）是美国最常见的妇科恶性肿瘤。TP 53突变型UC导致不成比例的死亡，这是由于对这些肿瘤的治疗有限以及缺乏对其基本脆弱性的机械理解。在这里，我们试图了解UC中TP 53突变的功能和治疗相关性。我们在一组TP 53突变型UC细胞系和患者源性类器官中功能性分析了靶向TP 53依赖性DNA损伤修复和细胞周期控制途径。在DNA损伤修复途径中没有一致的缺陷。相反，大多数模型表明依赖于有缺陷的G2/M细胞周期检查点和随后的极光激酶-LKB 1-p53-AKT信号在基线有丝分裂缺陷的设置上调。这种组合使它们对Aurora激酶抑制敏感。耐药细胞系表现出完整的G2/M检查点，结合Aurora激酶和WEE 1抑制剂，然后通过Aurora激酶诱导的纺锤体缺陷推动这些细胞进行有丝分裂，导致这些情况下的细胞凋亡。总体而言，这项工作提出了极光激酶抑制剂单独或与WEE 1抑制剂组合作为TP 53突变UC的相关机制驱动疗法。G2/M检查点的背景特异性功能评估可以作为识别Aurora激酶抑制剂敏感性肿瘤的生物标志物。
Cancers arising from the lining of the uterus, endometrial cancers, are the most common gynecologic malignancy in the United States. Once endometrial cancer escapes the uterus and grows in distant locations, there are limited therapeutic options. The most aggressive and lethal endometrial cancers carry alterations in the protein p53, which is a critical guardian of many cellular functions. The role of these p53 alterations in endometrial cancer is not well understood. The goal of this work was to use p53 altered models of endometrial cancer to understand which, if any, therapeutically targetable vulnerabilities these p53 alterations may confer in endometrial cancer. Here we show that many of these p53 altered cells have problems with cell division which can be targeted with novel single and combination therapies. These discoveries may lead to relevant new therapies for difficult to treat advanced stage endometrial cancers. Uterine carcinoma (UC) is the most common gynecologic malignancy in the United States. TP53 mutant UCs cause a disproportionate number of deaths due to limited therapies for these tumors and the lack of mechanistic understanding of their fundamental vulnerabilities. Here we sought to understand the functional and therapeutic relevance of TP53 mutations in UC. We functionally profiled targetable TP53 dependent DNA damage repair and cell cycle control pathways in a panel of TP53 mutant UC cell lines and patient-derived organoids. There were no consistent defects in DNA damage repair pathways. Rather, most models demonstrated dependence on defective G2/M cell cycle checkpoints and subsequent upregulation of Aurora kinase-LKB1-p53-AKT signaling in the setting of baseline mitotic defects. This combination makes them sensitive to Aurora kinase inhibition. Resistant lines demonstrated an intact G2/M checkpoint, and combining Aurora kinase and WEE1 inhibitors, which then push these cells through mitosis with Aurora kinase inhibitor-induced spindle defects, led to apoptosis in these cases. Overall, this work presents Aurora kinase inhibitors alone or in combination with WEE1 inhibitors as relevant mechanism driven therapies for TP53 mutant UCs. Context specific functional assessment of the G2/M checkpoint may serve as a biomarker in identifying Aurora kinase inhibitor sensitive tumors.
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影响因子：
5.2
作者：
Lahalle A;Lacroix M;De Blasio C;Cissé MY;Linares LK;Le Cam L
通讯作者：
Le Cam L
影响因子：
64.8
作者：
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--
影响因子：
28.2
作者：
Hill SJ;Decker B;Roberts EA;Horowitz NS;Muto MG;Worley MJ Jr;Feltmate CM;Nucci MR;Swisher EM;Nguyen H;Yang C;Morizane R;Kochupurakkal BS;Do KT;Konstantinopoulos PA;Liu JF;Bonventre JV;Matulonis UA;Shapiro GI;Berkowitz RS;Crum CP;D'Andrea AD
通讯作者：
D'Andrea AD
影响因子：
11.5
作者：
Lee, Jong Woo;Parameswaran, Janaki;Burtness, Barbara
通讯作者：
Burtness, Barbara
影响因子：
5.3
作者：
Hill, Sarah J.;Clark, Allison P.;Livingston, David M.
通讯作者：
Livingston, David M.