Purpose: We investigated why three patient-derived xenograft (PDX) childhood BRAFV600E-mutant brain tumor models are highly sensitive to trametinib. Mechanisms of acquired resistance selected in situ, and approaches to prevent resistance were also examined, which may translate to both low-grade glioma (LGG) molecular subtypes. Experimental Design: Sensitivity to trametinib [MEK inhibitor (MEKi)] alone or in combination with rapamycin (TORC1 inhibitor), was evaluated in pediatric PDX models. The effect of combined treatment of trametinib with rapamycin on development of trametinib resistance in vivo was examined. PDX tissue and tumor cells from trametinib-resistant xenografts were characterized. Results: In pediatric models TORC1 is activated through ERK-mediated inactivation of the tuberous sclerosis complex (TSC): consequently inhibition of MEK also suppressed TORC1 signaling. Trametinib-induced tumor regression correlated with dual inhibition of MAPK/TORC1 signaling, and decoupling TORC1 regulation from BRAF/MAPK control conferred trametinib resistance. In mice, acquired resistance to trametinib developed within three cycles of therapy in all three PDX models. Resistance to trametinib developed in situ is tumor-cell–intrinsic and the mechanism was tumor line specific. Rapamycin retarded or blocked development of resistance. Conclusions: In these three pediatric BRAF-mutant brain tumors, TORC1 signaling is controlled by the MAPK cascade. Trametinib suppressed both MAPK/TORC1 pathways leading to tumor regression. While low-dose intermittent rapamycin to enhance inhibition of TORC1 only modestly enhanced the antitumor activity of trametinib, it prevented or retarded development of trametinib resistance, suggesting future therapeutic approaches using rapamycin analogs in combination with MEKis that may be therapeutically beneficial in both KIAA1549::BRAF- and BRAFV600E-driven gliomas.

中文翻译：

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MAPK 信号传导对 TORC1 的调节决定了儿科 BRAFV600E 脑肿瘤模型中对 Trametinib 的敏感性和获得性耐药性

目的：我们研究了为什么三种患者来源的异种移植（PDX）儿童 BRAFV600E 突变脑肿瘤模型对曲美替尼高度敏感。还检查了原位选择的获得性耐药机制以及预防耐药的方法，这可能会转化为低级别胶质瘤（LGG）分子亚型。实验设计：在儿科 PDX 模型中评估曲美替尼 [MEK 抑制剂 (MEKi)] 单独使用或与雷帕霉素（TORC1 抑制剂）联合使用的敏感性。研究了曲美替尼与雷帕霉素联合治疗对体内曲美替尼耐药性发展的影响。对来自曲美替尼耐药异种移植物的 PDX 组织和肿瘤细胞进行了表征。结果：在儿科模型中，TORC1 通过 ERK 介导的结节性硬化症复合体 (TSC) 失活而被激活：因此，抑制 MEK 也会抑制 TORC1 信号传导。曲美替尼诱导的肿瘤消退与 MAPK/TORC1 信号传导的双重抑制相关，并且将 TORC1 调节与 BRAF/MAPK 控制解耦会导致曲美替尼耐药。在小鼠中，所有三种 PDX 模型在三个治疗周期内均出现了对曲美替尼的获得性耐药。原位产生的曲美替尼耐药性是肿瘤细胞固有的，其机制是肿瘤系特异性的。雷帕霉素可延缓或阻止耐药性的发展。结论：在这三种 BRAF 突变儿童脑肿瘤中，TORC1 信号传导受 MAPK 级联控制。Trametinib 抑制 MAPK/TORC1 通路，导致肿瘤消退。虽然低剂量间歇性雷帕霉素增强 TORC1 抑制作用仅适度增强曲美替尼的抗肿瘤活性，但它可以预防或延缓曲美替尼耐药性的发展，这表明未来使用雷帕霉素类似物与 MEK 组合的治疗方法可能对 KIAA1549 和 KIAA1549 都有治疗益处： BRAF 和 BRAFV600E 驱动的神经胶质瘤。