MNK Inhibition Sensitizes KRAS-Mutant Colorectal Cancer to mTORC1 Inhibition by Reducing eIF4E Phosphorylation and c-MYC Expression.
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ICR Authors
Authors
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
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
Document Type
Journal Article
Date
2021-05-01
Date Accepted
2020-12-11
Abstract
KRAS-mutant colorectal cancers 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 colorectal cancer. 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 colorectal cancers 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 cotargeting strategy with remarkable potency in multiple Kras-mutant mouse models and metastatic human organoids and identifies a patient population that may benefit from its clinical application. SIGNIFICANCE: KRAS mutation and elevated c-MYC are widespread in many tumors but remain predominantly untargetable. We find that mutant KRAS modulates translation, culminating in increased expression of c-MYC. We describe an effective strategy targeting mTORC1 and MNK in KRAS-mutant mouse and human models, pathways that are also commonly co-upregulated in colorectal cancer.This article is highlighted in the In This Issue feature, p. 995.
Citation
Cancer discovery, 2020
Source Title
Publisher
AMER ASSOC CANCER RESEARCH
ISSN
2159-8274
eISSN
2159-8290
Collections
Research Team
Gastrointestinal Cancer Biology and Genomics
Gastrointestinal Cancer Biology and Genomics
Gastrointestinal Cancer Biology and Genomics