Greehey Children's Cancer Research Institute, UT Health, San Antonio, Texas.
Center for Childhood Cancer and Blood Diseases, Nationwide Children's Hospital, Columbus, Ohio.
Clin Cancer Res. 2022 Sep 1;28(17):3836-3849. doi: 10.1158/1078-0432.CCR-22-1052.
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.
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.
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.
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.
我们研究了为什么三个源自患者的异种移植（PDX）儿童 BRAFV600E 突变脑肿瘤模型对曲美替尼非常敏感。还研究了原位选择的获得性耐药机制以及预防耐药的方法，这些方法可能适用于低级别胶质瘤（LGG）的两种分子亚型。
评估了曲美替尼（MEK 抑制剂（MEKi））单独或与雷帕霉素（TORC1 抑制剂）联合治疗对儿科 PDX 模型的敏感性。检查了曲美替尼联合雷帕霉素治疗对体内曲美替尼耐药发展的影响。对曲美替尼耐药异种移植的 PDX 组织和肿瘤细胞进行了特征分析。
在儿科模型中，TORC1 通过 ERK 介导的结节性硬化复合物（TSC）失活而被激活：因此，MEK 的抑制也抑制了 TORC1 信号。曲美替尼诱导的肿瘤消退与 MAPK/TORC1 信号的双重抑制相关，并且将 TORC1 调节与 BRAF/MAPK 控制解耦赋予了曲美替尼耐药性。在小鼠中，三种 PDX 模型中的所有模型在三个治疗周期内均出现对曲美替尼的获得性耐药。原位获得的耐药性是肿瘤细胞内在的，其机制是肿瘤细胞特异性的。雷帕霉素延缓或阻止了耐药性的发展。
在这三个儿科 BRAF 突变脑肿瘤中，TORC1 信号由 MAPK 级联控制。曲美替尼抑制了 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 的抑制作用仅适度增强了曲美替尼的抗肿瘤活性，但它预防或延缓了曲美替尼耐药性的发展，这表明未来使用雷帕霉素类似物联合 MEKi 的治疗方法可能对 KIAA1549::BRAF-和 BRAFV600E 驱动的神经胶质瘤具有治疗益处。
