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Cooperative Blockade of CK2 and ATM Kinases Drives Apoptosis in VHL-Deficient Renal Carcinoma Cells through ROS Overproduction

CK2 和 ATM 激酶的協(xié)同阻斷通過 ROS 過量產(chǎn)生驅(qū)動 VHL 缺陷型腎癌細胞凋亡

Renal cell carcinoma (RCC) is the eighth leading malignancy in the world, accounting for 4% of all cancers with poor outcome when metastatic. Protein kinases are highly druggable proteins, which are often aberrantly activated in cancers. The aim of our study was to identify candidate targets for metastatic clear cell renal cell carcinoma therapy, using chemo-genomic-based high-throughput screening. We found that the combined inhibition of the CK2 and ATM kinases in renal tumor cells and patient-derived tumor samples induces synthetic lethality. Mechanistic investigations unveil that this drug combination triggers apoptosis through HIF-2α-(Hypoxic inducible factor HIF-2α) dependent reactive oxygen species (ROS) overproduction, giving a new option for patient care in metastatic RCC.

腎細胞癌 (RCC) 是世界上第八大惡性腫瘤，占所有轉(zhuǎn)移性預(yù)后不良癌癥的 4%。蛋白激酶是高度可藥用的蛋白質(zhì)，通常在癌癥中被異常激活。我們研究的目的是使用基于化學(xué)基因組的高通量篩選來確定轉(zhuǎn)移性透明細胞腎細胞癌治療的候選靶點。我們發(fā)現(xiàn)在腎腫瘤細胞和患者來源的腫瘤樣本中聯(lián)合抑制 CK2 和 ATM 激酶可誘導(dǎo)合成致死率。機制研究表明，這種藥物組合通過 HIF-2α-（缺氧誘導(dǎo)因子 HIF-2α）依賴性活性氧（ROS）過量產(chǎn)生觸發(fā)細胞凋亡，為轉(zhuǎn)移性腎細胞癌的患者護理提供了新的選擇。

T75細胞培養(yǎng)瓶

Kinase-targeted agents demonstrate antitumor activity in advanced metastatic clear cell renal cell carcinoma (ccRCC), which remains largely incurable. Integration of genomic approaches through small-molecules and genetically based high-throughput screening holds the promise of improved discovery of candidate targets for cancer therapy. The 786-O cell line represents a model for most ccRCC that have a loss of functional pVHL (von Hippel-Lindau). A multiplexed assay was used to study the cellular fitness of a panel of engineered ccRCC isogenic 786-O VHL? cell lines in response to a collection of targeted cancer therapeutics including kinase inhibitors, allowing the interrogation of over 2880 drug–gene pairs. Among diverse patterns of drug sensitivities, investigation of the mechanistic effect of one selected drug combination on tumor spheroids and ex vivo renal tumor slice cultures showed that VHL-defective ccRCC cells were more vulnerable to the combined inhibition of the CK2 and ATM kinases than wild-type VHL cells. Importantly, we found that HIF-2α acts as a key mediator that potentiates the response to combined CK2/ATM inhibition by triggering ROS-dependent apoptosis. Importantly, our findings reveal a selective killing of VHL-deficient renal carcinoma cells and provide a rationale for a mechanism-based use of combined CK2/ATM inhibitors for improved patient care in metastatic VHL-ccRCC.

靶向激酶的藥物在晚期轉(zhuǎn)移性透明細胞腎細胞癌 (ccRCC) 中表現(xiàn)出抗腫瘤活性，而這在很大程度上仍然無法治愈。通過小分子和基于遺傳的高通量篩選整合基因組方法有望改進癌癥治療候選靶點的發(fā)現(xiàn)。786-O 細胞系代表了大多數(shù)功能性 pVHL 缺失的 ccRCC 模型 (von Hippel-Lindau)。使用多重測定來研究一組工程化 ccRCC 同基因 786-O VHL 的細胞適應(yīng)性-細胞系響應(yīng)包括激酶抑制劑在內(nèi)的一系列靶向癌癥治療，允許對超過 2880 種藥物-基因?qū)M行研究。在多種藥物敏感性模式中，對一種選定藥物組合對腫瘤球體和離體腎腫瘤切片培養(yǎng)物的機制影響的研究表明，與野生型相比，VHL 缺陷型 ccRCC 細胞更容易受到 CK2 和 ATM 激酶聯(lián)合抑制的影響。型 VHL 細胞。重要的是，我們發(fā)現(xiàn) HIF-2α 作為一種關(guān)鍵介質(zhì)，通過觸發(fā) ROS 依賴性細胞凋亡來增強對聯(lián)合 CK2/ATM 抑制的反應(yīng)。重要的是，我們的研究結(jié)果揭示了 VHL 缺陷型腎癌細胞的選擇性殺傷，并為基于機制的 CK2/ATM 抑制劑聯(lián)合使用以改善轉(zhuǎn)移性 VHL-ccRCC 的患者護理提供了依據(jù)。

細胞工廠

Genomic analyses have revealed relationships between synthetic lethal interactions and genetic lesions that may be exploited therapeutically [21]. Chemo-genetic screens revealed CK2 and ATM kinases as synthetic lethal targets in VHL-deficient renal carcinoma cells. This vulnerability was characterized using various models, including cells grown as monolayers, tumor spheroid cultures and tumor tissue slices from xenografts and clinical patient samples. Combined inhibition of CK2 and ATM eliminated VHL-deficient renal carcinoma cells by increasing NOX4-mediated ROS production. Importantly, HIF-2α acts as a key determinant that potentiates this response. Overall, given the demonstrated safety of CX-4945 in initial human studies, these preclinical data may justify the implementation of clinical trials using CX-4945 in combination with ATM inhibitors in a subset of HIF-2α-expressing VHL-defective ccRCC patients. Our findings have translational implications which are currently evaluated in the frame of the preclinical trial NCT03571438 .

基因組分析揭示了合成致死相互作用與可用于治療的遺傳損傷之間的關(guān)系 [ 21]?；瘜W(xué)遺傳學(xué)篩選顯示 CK2 和 ATM 激酶是 VHL 缺陷型腎癌細胞中的合成致死靶標(biāo)。使用各種模型來表征這種脆弱性，包括生長為單層的細胞、腫瘤球體培養(yǎng)物和來自異種移植物和臨床患者樣本的腫瘤組織切片。CK2 和 ATM 的聯(lián)合抑制通過增加 NOX4 介導(dǎo)的 ROS 產(chǎn)生來消除 VHL 缺陷型腎癌細胞。重要的是，HIF-2α 是增強這種反應(yīng)的關(guān)鍵決定因素。總體而言，鑒于 CX-4945 在最初的人體研究中被證明是安全的，這些臨床前數(shù)據(jù)可能證明使用 CX-4945 與 ATM 抑制劑聯(lián)合在表達 HIF-2α 的 VHL 缺陷型 ccRCC 患者的子集中實施臨床試驗是合理的。

細胞培養(yǎng)板

關(guān)鍵詞： ccRCC, 自動柜員機,CK2 ; 激酶抑制劑,HIF-2α；活性氧途徑,NOX4,細胞凋亡,腫瘤組織切片, ccRCC; ATM,CK2, kinase inhibitor,HIF-2α,ROS pathway,NOX4,apoptosis, tumor tissue slices

來源：MDPI https://www.mdpi.com/2072-6694/13/3/576