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Crenolanib Regulates ERK and AKT/mTOR Signaling Pathways in RAS/BRAF-Mutated Colorectal Cancer Cells and Organoids
Molecular Cancer Research ( IF 5.2 ) Pub Date : 2021-05-01 , DOI: 10.1158/1541-7786.mcr-20-0600
Shiki Fujino 1, 2 , Norikatsu Miyoshi 1, 2 , Aya Ito 2 , Masayoshi Yasui 3 , Masayuki Ohue 3 , Takayuki Ogino 1 , Hidekazu Takahashi 1 , Mamoru Uemura 1 , Chu Matsuda 1 , Tsunekazu Mizushima 1 , Yuichiro Doki 1 , Hidetoshi Eguchi 1
Affiliation  

Recently developed molecularly targeted therapies such as EGFR inhibitors have notably improved the prognosis of patients with cancer. However, patients with KRAS and BRAF mutations do not currently benefit from these therapies. Here, we aimed to examine potential effects of crenolanib as a new molecularly targeted therapy in colorectal cancer. We used multiple colorectal cancer cell lines to investigate the growth-inhibitory effect of crenolanib and its effect in combination with other cytotoxic agents. Primary cultures of patient-derived organoids (PDO), a model that reflects the heterogeneity of clinical colorectal cancer, were used to further validate the effects of crenolanib. Unlike cetuximab, crenolanib remarkably suppressed ERK and AKT/mTOR pathways in HT29 cells with BRAF mutation and in HCT116 cells with KRAS mutation with corresponding growth-suppressing effects. Additive or synergistic effects were observed in treatments with combination of crenolanib and other cytotoxic drugs. Moreover, crenolanib suppressed the expression of stem cell markers, such as OCT4, NANOG, and SOX2. These observations were substantiated in seven PDOs with KRAS mutation and two PDOs without KRAS/BRAF mutations, with crenolanib suppressing the growth of all PDOs regardless of their KRAS mutation status. Furthermore, crenolanib abrogated PDGF- and TGFβ-induced increase of OCT4-positive cells in PDOs. Together, these findings suggest that crenolanib may have clinical utility for patients with colorectal cancer, especially patients with KRAS/BRAF mutations. Implications: These findings indicate that crenolanib can be a useful target agent for patients with colorectal cancer, especially patients with KRAS/BRAF mutations.

中文翻译:

Crenolanib 调节 RAS/BRAF 突变的结直肠癌细胞和类器官中的 ERK 和 AKT/mTOR 信号通路

最近开发的分子靶向疗法如EGFR抑制剂显着改善了癌症患者的预后。然而,具有 KRAS 和 BRAF 突变的患者目前并未从这些疗法中受益。在这里,我们旨在检查 crenolanib 作为一种新的分子靶向治疗结直肠癌的潜在作用。我们使用多种结直肠癌细胞系来研究克雷诺拉尼的生长抑制作用及其与其他细胞毒剂联合使用的作用。患者来源的类器官 (PDO) 的原代培养物是一种反映临床结直肠癌异质性的模型,用于进一步验证 crenolanib 的作用。与西妥昔单抗不同,在具有 BRAF 突变的 HT29 细胞和具有 KRAS 突变的 HCT116 细胞中,crenolanib 显着抑制 ERK 和 AKT/mTOR 通路,并具有相应的生长抑制作用。在与 crenolanib 和其他细胞毒性药物联合治疗时观察到相加或协同作用。此外,crenolanib 抑制干细胞标志物的表达,如 OCT4、NANOG 和 SOX2。这些观察结果在 7 个具有 KRAS 突变的 PDO 和两个没有 KRAS/BRAF 突变的 PDO 中得到证实,无论其 KRAS 突变状态如何,crenolanib 都抑制所有 PDO 的生长。此外,crenolanib 消除了 PDGF 和 TGFβ 诱导的 PDO 中 OCT4 阳性细胞的增加。总之,这些研究结果表明,crenolanib 可能对结直肠癌患者具有临床效用,尤其是具有 KRAS/BRAF 突变的患者。
更新日期:2021-05-04
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