Neddylation inhibition sensitises renal medullary carcinoma tumours to platinum chemotherapy.
Neddylation inhibition sensitises renal medullary carcinoma tumours to platinum chemotherapy.
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DOI：
10.1002/ctm2.1267
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发表时间：
2023-05
影响因子：
10.6
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中科院分区：
文献类型：
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肾髓样癌（RMC）是一种高度侵袭性的癌症，需要新的治疗策略。类化修饰途径可以保护细胞免受RMC中铂基化疗引起的DNA损伤。我们研究了培酮远地抑制类化修饰是否会协同增强RMC中铂基化疗的抗肿瘤作用。我们在RMC细胞系中体外评估了类化活化酶抑制剂pevonedistat的IC50浓度。Bliss协同评分是通过生长抑制试验计算的，在使用不同浓度的培酮远地和卡铂治疗后。western blot和免疫荧光法检测蛋白表达。在铂- naïve和铂-经验的患者衍生异种移植（PDX） RMC模型中，评估了佩酮远他单独或联合铂基化疗的疗效。RMC细胞系显示派伏酮的IC50浓度远低于人的最大耐受剂量。当与卡铂联合使用时，派福尼远地表现出显著的体外协同效应。卡铂单独治疗增加了用于修复由铂盐引起的链间交联的核ERCC1水平。相反，在卡铂中加入佩酮远会导致p53上调，导致FANCD2抑制和核ERCC1水平降低。在铂基化疗中加入培酮远地可显著抑制铂- naïve和铂-经历的RMC PDX模型的肿瘤生长（p < 0.01）。我们的研究结果表明，佩维奈远与卡铂协同作用，通过抑制DNA损伤修复来抑制RMC细胞和肿瘤的生长。这些发现支持了一项临床试验的开展，该试验将佩维奈远与铂基化疗联合用于RMC。pevonedistat对类化修饰的抑制增强了铂基化疗在肾髓质癌（RMC）细胞系和患者来源的异种移植物中的体外和体内抗肿瘤作用。佩onedistat诱导p53介导的FANCD2抑制，导致DNA损伤部位ERCC1募集减少。佩维酮远地抑制铂诱导的DNA损伤修复增加RMC细胞凋亡。关键点:
Renal medullary carcinoma (RMC) is a highly aggressive cancer in need of new therapeutic strategies. The neddylation pathway can protect cells from DNA damage induced by the platinum‐based chemotherapy used in RMC. We investigated if neddylation inhibition with pevonedistat will synergistically enhance antitumour effects of platinum‐based chemotherapy in RMC. We evaluated the IC50 concentrations of the neddylation‐activating enzyme inhibitor pevonedistat in vitro in RMC cell lines. Bliss synergy scores were calculated using growth inhibition assays following treatment with varying concentrations of pevonedistat and carboplatin. Protein expression was assessed by western blot and immunofluorescence assays. The efficacy of pevonedistat alone or in combination with platinum‐based chemotherapy was evaluated in vivo in platinum‐naïve and platinum‐experienced patient‐derived xenograft (PDX) models of RMC. The RMC cell lines demonstrated IC50 concentrations of pevonedistat below the maximum tolerated dose in humans. When combined with carboplatin, pevonedistat demonstrated a significant in vitro synergistic effect. Treatment with carboplatin alone increased nuclear ERCC1 levels used to repair the interstrand crosslinks induced by platinum salts. Conversely, the addition of pevonedistat to carboplatin led to p53 upregulation resulting in FANCD2 suppression and reduced nuclear ERCC1 levels. The addition of pevonedistat to platinum‐based chemotherapy significantly inhibited tumour growth in both platinum‐naïve and platinum‐experienced PDX models of RMC (p < .01). Our results suggest that pevonedistat synergises with carboplatin to inhibit RMC cell and tumour growth through inhibition of DNA damage repair. These findings support the development of a clinical trial combining pevonedistat with platinum‐based chemotherapy for RMC. Inhibition of neddylation by pevonedistat enhances the in vitro and in vivo antitumor effects of platinum‐based chemotherapy in renal medullary carcinoma (RMC) cell lines and patient derived xenografts. Pevonedistat induces p53‐mediated suppression of FANCD2 resulting in reduction of ERCC1 recruitment at locations of DNA damage. Inhibition by pevonedistat of platinum‐induced DNA damage repair increases RMC cellular apoptosis. Critical points:
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影响因子：
46.9
作者：
Doench JG;Fusi N;Sullender M;Hegde M;Vaimberg EW;Donovan KF;Smith I;Tothova Z;Wilen C;Orchard R;Virgin HW;Listgarten J;Root DE
通讯作者：
Root DE
影响因子：
14.9
作者：
Loughery J;Cox M;Smith LM;Meek DW
通讯作者：
Meek DW
影响因子：
2.1
作者：
Msaouel, Pavlos;Walker, Cheryl L.;Tannir, Nizar M.
通讯作者：
Tannir, Nizar M.
影响因子：
8.8
作者：
Calandrini, Camilla;van Hooff, Sander R.;Drost, Jarno
通讯作者：
Drost, Jarno
影响因子：
16.6
作者：
Maghames CM;Lobato-Gil S;Perrin A;Trauchessec H;Rodriguez MS;Urbach S;Marin P;Xirodimas DP
通讯作者：
Xirodimas DP