MNK Inhibition Sensitizes KRAS-Mutant Colorectal Cancer to mTORC1 Inhibition by Reducing eIF4E Phosphorylation and c-MYC Expression.
MNK Inhibition Sensitizes KRAS-Mutant Colorectal Cancer to mTORC1 Inhibition by Reducing eIF4E Phosphorylation and c-MYC Expression.
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DOI：
10.1158/2159-8290.cd-20-0652
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发表时间：
2021-05
期刊：
影响因子：
28.2
通讯作者：
Sansom OJ
中科院分区：
文献类型：
--
作者：
Knight JRP;Alexandrou C;Skalka GL;Vlahov N;Pennel K;Officer L;Teodosio A;Kanellos G;Gay DM;May-Wilson S;Smith EM;Najumudeen AK;Gilroy K;Ridgway RA;Flanagan DJ;Smith RCL;McDonald L;MacKay C;Cheasty A;McArthur K;Stanway E;Leach JD;Jackstadt R;Waldron JA;Campbell AD;Vlachogiannis G;Valeri N;Haigis KM;Sonenberg N;Proud CG;Jones NP;Swarbrick ME;McKinnon HJ;Faller WJ;Le Quesne J;Edwards J;Willis AE;Bushell M;Sansom OJ
KRAS 突变结直肠癌 (CRC) 对治疗有抵抗力，这对约 40% 的病例来说是一个重大问题。 Rapalogs 可抑制 mTORC1 从而抑制蛋白质合成，但在 KRAS 突变 CRC 中的疗效明显较差。使用 Kras 突变小鼠模型以及小鼠和患者来源的类器官，我们证明具有 G12D 突变的 KRAS 从根本上重新连接翻译，以增加体积和 mRNA 特异性翻译起始。这是通过 MNK/eIF4E 途径发生的，最终导致 c-MYC 的持续表达。通过对该通路的遗传和小分子靶向，我们通过抑制 c-MYC 使 KRASG12D 模型对雷帕霉素高度敏感。我们发现 45% 的 CRC 通过 mTORC1 和 MNK 具有高信号传导，这一特征与一部分患者的癌症特异性生存期缩短 3.5 年相关。这项工作提供了一种依赖于 c-MYC 的共靶向策略，在多种 Kras 突变小鼠模型和转移性人类类器官中具有显着的效力，并确定了可能受益于其临床应用的患者群体。
KRAS-mutant colorectal cancers (CRC) are resistant to therapeutics, presenting a significant problem for ~40% of cases. Rapalogs, which inhibit mTORC1 and thus protein synthesis, are significantly less potent in KRAS-mutant CRC. Using Kras-mutant mouse models and mouse- and patient-derived organoids we demonstrate that KRAS with G12D mutation fundamentally rewires translation to increase both bulk and mRNA-specific translation initiation. This occurs via the MNK/eIF4E pathway culminating in sustained expression of c-MYC. By genetic and small molecule targeting of this pathway, we acutely sensitize KRASG12D models to rapamycin via suppression of c-MYC. We show that 45% of CRCs have high signaling through mTORC1 and the MNKs, with this signature correlating with a 3.5-year shorter cancer-specific survival in a subset of patients. This work provides a c-MYC-dependent co-targeting strategy with remarkable potency in multiple Kras-mutant mouse models and metastatic human organoids and identifies a patient population who may benefit from its clinical application.
影响因子：
3.7
作者：
Marzec M;Liu X;Wysocka M;Rook AH;Odum N;Wasik MA
通讯作者：
Wasik MA