Lock Rebecca, Ingraham Rachel, Maertens Ophélia, Miller Abigail L, Weledji Nelly, Legius Eric, Konicek Bruce M, Yan Sau-Chi B, Graff Jeremy R, Cichowski Karen
J Clin Invest. 2016 Jun 1;126(6):2181-90. doi: 10.1172/JCI85183. Epub 2016 May 9.
Neurofibromin 1-mutant (NF1-mutant) cancers are driven by excessive Ras signaling; however, there are currently no effective therapies for these or other Ras-dependent tumors. While combined MEK and mTORC1 suppression causes regression of NF1-deficient malignancies in animal models, the potential toxicity of cotargeting these 2 major signaling pathways in humans may necessitate the identification of more refined, cancer-specific signaling nodes. Here, we have provided evidence that MAPK-interacting kinases (MNKs), which converge on the mTORC1 effector eIF4E, are therapeutic targets in NF1-deficient malignancies. Specifically, we evaluated primary human NF1-deficient peripheral nervous system tumors and found that MNKs are activated in the majority of tumors tested. Genetic and chemical suppression of MNKs in NF1-deficient murine tumor models and human cell lines potently cooperated with MEK inhibitors to kill these cancers through effects on eIF4E. We also demonstrated that MNK kinases are important and direct targets of cabozantinib. Accordingly, coadministration of cabozantinib and MEK inhibitors triggered dramatic regression in an aggressive genetically engineered tumor model. The cytotoxicity of this combination required the suppression of MNK-induced eIF4E phosphorylation and was not recapitulated by suppressing other cabozantinib targets. Collectively, these studies demonstrate that combined MNK and MEK suppression represents a promising therapeutic strategy for these incurable Ras-driven tumors and highlight the utility of developing selective MNK inhibitors for these and possibly other malignancies.
神经纤维瘤蛋白1突变型（NF1突变型）癌症由过度的Ras信号传导驱动；然而，目前对于这些癌症或其他Ras依赖性肿瘤尚无有效的治疗方法。虽然在动物模型中联合抑制MEK和mTORC1可使NF1缺陷型恶性肿瘤消退，但在人类中同时靶向这两条主要信号通路的潜在毒性可能需要确定更精细的、癌症特异性的信号节点。在此，我们提供了证据表明，汇聚于mTORC1效应因子eIF4E的丝裂原活化蛋白激酶相互作用激酶（MNKs）是NF1缺陷型恶性肿瘤的治疗靶点。具体而言，我们评估了原发性人类NF1缺陷型外周神经系统肿瘤，发现MNKs在大多数测试肿瘤中被激活。在NF1缺陷型小鼠肿瘤模型和人类细胞系中对MNKs进行基因和化学抑制，可通过对eIF4E的作用与MEK抑制剂有效协同作用来杀死这些癌症。我们还证明MNK激酶是卡博替尼的重要且直接的靶点。因此，在一个侵袭性基因工程肿瘤模型中，联合给予卡博替尼和MEK抑制剂引发了显著的肿瘤消退。这种联合用药的细胞毒性需要抑制MNK诱导的eIF4E磷酸化，而抑制卡博替尼的其他靶点并不能重现这种效果。总体而言，这些研究表明联合抑制MNK和MEK代表了一种针对这些无法治愈的Ras驱动肿瘤的有前景的治疗策略，并突出了开发针对这些以及可能其他恶性肿瘤的选择性MNK抑制剂的实用性。
