UNASSIGNED: To address this need, we tested the efficacy of a novel non-TKI compound, OPB-171775, using patient-derived xenograft models of GISTs. In parallel, we sought to elucidate the mechanism of action of the compound.
UNASSIGNED: Our study revealed that OPB-171775 exhibited significant efficacy against GISTs regardless of their KIT mutation status by inducing complex formation between phosphodiesterase 3A (PDE3A) and Schlafen family member 12 (SLFN12), which are highly expressed in GISTs, leading to SLFN12 RNase-mediated cell death. Furthermore, we identified the activation of general control non-derepressible 2 and its downstream response as an effector pathway of SLFN12 in mediating anticancer activity and revealed potential pharmacodynamic markers.
UNASSIGNED: These findings suggest that OPB-171775, with its significant efficacy, could potentially serve as a novel and effective treatment option for advanced GISTs, particularly those resistant to TKIs.
方法:为了满足这一需求,我们测试了一种新型非TKI化合物的功效,OPB-171775,使用患者来源的GIST异种移植模型。并行,我们试图阐明该化合物的作用机制.
结果:我们的研究表明,OPB-171775通过诱导磷酸二酯酶3A(PDE3A)和Schlafen家族成员12(SLFN12)之间的复合物形成,无论其KIT突变状态如何,对GIST都表现出明显的疗效。在GIST中高度表达,导致SLFN12核糖核酸酶介导的细胞死亡。此外,我们确定了一般对照非抑制型2(GCN2)的激活及其下游反应作为SLFN12介导抗癌活性的效应途径,并揭示了潜在的药效学标志物.
结论:这些研究结果表明,OPB-171775具有显著的疗效,有可能成为一种新的和有效的治疗方案,为先进的GIST,尤其是那些对TKIs有抵抗力的.