FBXW7 regulates the sensitivity of imatinib in gastrointestinal stromal tumors by targeting MCL1,Gastric Cancer

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FBXW7 regulates the sensitivity of imatinib in gastrointestinal stromal tumors by targeting MCL1
Gastric Cancer ( IF 6.0 ) Pub Date : 2023-12-24 , DOI: 10.1007/s10120-023-01454-6
Xiyu Wu ₁ , Masaaki Iwatsuki ₁ , Masakazu Takaki ₂ , Takuro Saito ₃ , Tsutomu Hayashi ₄ , Masato Kondo ₅ , Yoshiharu Sakai ₆ , Naoto Gotohda ₇ , Eiji Tanaka ₈ , Toshirou Nishida ₉ , Hideo Baba ₁

Affiliation

Background

Imatinib contributes to improving prognosis of high-risk or unresectable gastrointestinal stromal tumors (GISTs). As therapeutic efficacy is limited by imatinib resistance and toxicity, the exploration of predictive markers of imatinib therapeutic efficacy that enables patients to utilize more effective therapeutic strategies remains urgent.

Methods

The correlation between FBXW7 and imatinib resistance via FBXW7-MCL1 axis was evaluated in vitro and in vivo experiments. The significance of FBXW7 as a predictor of imatinib treatment efficacy was examined in 140 high-risk patients with GISTs.

Results

The ability of FBXW7 to predict therapeutic efficacy of adjuvant imatinib in high-risk GIST patients was determined through 5-year recurrence-free survival (RFS) rates analysis and multivariate analysis. FBXW7 affects imatinib sensitivity by regulating apoptosis in GIST-T1 cells. FBXW7 targets MCL1 to regulate apoptosis. MCL1 involves in the regulation of imatinib sensitivity through inhibiting apoptosis in GIST-T1 cells. FBXW7 regulates imatinib sensitivity by down-regulating MCL1 to enhance imatinib-induced apoptosis in vitro. FBXW7 regulates imatinib sensitivity of GIST cells by targeting MCL1 to predict efficacy of imatinib treatment in vivo.

Conclusions

FBXW7 regulates imatinib sensitivity by inhibiting MCL1 to enhance imatinib-induced apoptosis in GIST, and predicts efficacy of imatinib treatment in high-risk GIST patients treated with imatinib.

中文翻译：

FBXW7通过靶向MCL1调节伊马替尼在胃肠道间质瘤中的敏感性

背景

伊马替尼有助于改善高风险或不可切除的胃肠道间质瘤 (GIST) 的预后。由于治疗效果受到伊马替尼耐药性和毒性的限制，探索伊马替尼治疗效果的预测标志物以使患者能够利用更有效的治疗策略仍然紧迫。

方法

在体外和体内实验中评估了 FBXW7 和伊马替尼耐药性通过 FBXW7-MCL1 轴之间的相关性。在 140 名高危 GIST 患者中检查了 FBXW7 作为伊马替尼治疗效果预测因子的重要性。

结果

通过 5 年无复发生存 (RFS) 率分析和多变量分析确定 FBXW7 预测伊马替尼辅助治疗对高危 GIST 患者疗效的能力。 FBXW7 通过调节 GIST-T1 细胞的凋亡来影响伊马替尼敏感性。 FBXW7 靶向 MCL1 来调节细胞凋亡。 MCL1 通过抑制 GIST-T1 细胞凋亡来调节伊马替尼敏感性。 FBXW7 通过下调 MCL1 来调节伊马替尼敏感性，从而增强伊马替尼诱导的体外细胞凋亡。 FBXW7 通过靶向 MCL1 调节 GIST 细胞的伊马替尼敏感性，以预测伊马替尼治疗的体内疗效。