Efficacy of rigosertib, a small molecular RAS signaling disrupter for the treatment of KRAS-mutant colorectal cancer.
Efficacy of rigosertib, a small molecular RAS signaling disrupter for the treatment of KRAS-mutant colorectal cancer.
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rigosertib 是一种小分子 RAS 信号干扰剂，用于治疗 KRAS 突变结直肠癌的疗效。
DOI：
10.20892/j.issn.2095-3941.2020.0532
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发表时间：
2021-08-04
影响因子：
5.5
通讯作者：
Ding K
中科院分区：
文献类型：
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作者：
Zhou X;Xiao Q;Fu D;Zhang H;Tang Y;He J;Hu Y;Kong X;Teng F;Liu X;Yuan Y;Ding K
突变型KRAS是RAS的主要亚型，通过组构性激活RAF/MEK/ERK和PI3K/AKT通路，在结直肠癌的发生中起关键作用。迫切需要有效的靶向治疗。我们研究了rigosertib，一种苯甲酰基砜RAS信号干扰物，是否可以选择性地杀死kras突变的结直肠癌细胞。CCK-8检测细胞活力。采用患者源性肿瘤和癌细胞异种移植模型检测rigosertib的抑制效果。流式细胞术观察细胞凋亡和细胞周期进展。Western blot检测细胞凋亡和细胞周期阻滞标志物。DCFH-DA法测定活性氧。免疫组化染色和Western blot检测结直肠癌组织和细胞中RAS信号标志物的表达。Rigosertib （RGS）对结直肠癌细胞具有细胞毒性作用，在kras突变细胞中作用更大。此外，RGS诱导kras突变体DLD1和HCT116细胞有丝分裂阻滞和氧化应激依赖性凋亡。此外，RGS破坏RAS信号，RAS/MEK/ERK的抑制不依赖于细胞氧化应激。在患者来源的异种移植模型中，kras突变亚组中RGS的应答和肿瘤抑制作用显著提高，而RGS治疗肿瘤的p-MEK、p-ERK和p-AKT水平显著降低。最后，在kras突变，化疗耐药的患者来源的异种移植模型中，RGS比氟嘧啶+奥沙利铂/伊立替康+贝伐单抗的联合标准治疗显示出更强的治疗效果。这些数据表明，利用RGS靶向RAS信号可能是kras突变型结直肠癌患者的一种治疗方法。
Mutant KRAS, the principal isoform of RAS, plays a pivotal role in the oncogenesis of colorectal cancer by constitutively activating the RAF/MEK/ERK and PI3K/AKT pathways. Effective targeted therapies are urgently needed. We investigated whether rigosertib, a benzyl styryl sulfone RAS signaling disruptor, could selectively kill KRAS-mutant colorectal cancer cells. CCK-8 was used to determine the cell viability. Patient-derived tumor and cancer cell xenograft models were used to detect the inhibitory efficacy of rigosertib. Flow cytometry was used to evaluate the apoptosis and cell cycle progression. Apoptosis and cell cycle arrest markers were detected by Western blot. DCFH-DA was used to determine the reactive oxygen species. Immunohistochemistry staining and Western blot were performed to characterize RAS signaling markers in colorectal cancer tissues and cells. Rigosertib (RGS) exhibited a cytotoxic effect against colorectal cancer cells, which was greater in KRAS-mutant cells. Furthermore, RGS induced mitotic arrest and oxidative stress-dependent apoptosis in KRAS-mutant DLD1 and HCT116 cells. Besides, RGS disrupted RAS signaling, and the inhibition of RAS/MEK/ERK was independent of cellular oxidative stress. Using patient-derived xenograft models, the response and tumor inhibition of RGS were significantly higher in the KRAS-mutant subgroup, while p-MEK, p-ERK, and p-AKT levels of RGS-treated tumors were significantly decreased. Finally, in a KRAS-mutant, chemotherapy-resistant patient-derived xenograft model, RGS showed a stronger therapeutic effect than the combination standard therapy involving fluoropyrimidine + oxaliplatin/irinotecan + bevacizumab. These data showed that targeting RAS signaling using RGS could be a therapeutic treatment for KRAS-mutant colorectal cancer patients.
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影响因子：
5.7
作者：
Hyoda T;Tsujioka T;Nakahara T;Suemori S;Okamoto S;Kataoka M;Tohyama K
通讯作者：
Tohyama K
影响因子：
7.3
作者：
Reddy MV;Venkatapuram P;Mallireddigari MR;Pallela VR;Cosenza SC;Robell KA;Akula B;Hoffman BS;Reddy EP
通讯作者：
Reddy EP
有效使用 PI3K 和 MEK 抑制剂治疗突变型 Kras G12D 和 PIK3CA H1047R 小鼠肺癌。
影响因子：
82.9
作者：
通讯作者：
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影响因子：
5.7
作者：
Ganesan P;Janku F;Naing A;Hong DS;Tsimberidou AM;Falchook GS;Wheler JJ;Piha-Paul SA;Fu S;Stepanek VM;Lee JJ;Luthra R;Overman MJ;Kopetz ES;Wolff RA;Kurzrock R
通讯作者：
Kurzrock R
DOI：
10.1038/nrc3106
发表时间：
2011-10-13
期刊：
Nature reviews. Cancer
影响因子：
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作者：
通讯作者：
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