MNK inhibition sensitizes KRAS-mutant colorectal cancer to mTORC1 inhibition by reducing eIF4E phosphorylation and c-MYC expression

Knight, J. R.P. et al. (2021) MNK inhibition sensitizes KRAS-mutant colorectal cancer to mTORC1 inhibition by reducing eIF4E phosphorylation and c-MYC expression. Cancer Discovery, 11(5), pp. 1228-1247. (doi: 10.1158/2159-8290.CD-20-0652) (PMID:33328217)

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Abstract

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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:May-Wilson, Sebastian and Leach, Dr Joshua and Le Quesne, Professor John and Pennel, Kathryn and Edwards, Professor Joanne and Smith, Rachael and Ridgway, Dr Rachel and Valeri, Dr Nicola and Skalka, Dr George and Gilroy, Dr Kathryn and Faller, Dr William and Gay, David and McDonald, Dr Laura and Sansom, Professor Owen and Bushell, Professor Martin and McKinnon, Dr Heather and Campbell, Dr Andrew
Authors: Knight, J. R.P., Alexandrou, C., Skalka, G. L., Vlahov, N., Pennel, K., Officer, L., Teodosio, A., Kanellos, G., Gay, D. M., May-Wilson, S., Smith, E. M., Najumudeen, A. K., Gilroy, K., Ridgway, R. A., Flanagan, D. J., Smith, R. C.L., McDonald, L., MacKay, C., Cheasty, A., McArthur, K., Stanway, E., Leach, J. D.G., Jackstadt, R., Waldron, J. A., Campbell, A. D., Vlachogiannis, G., Valeri, N., Haigis, K. M., Sonenberg, N., Proud, C. G., Jones, N. P., Swarbrick, M. E., McKinnon, H. J., Faller, W. J., Le Quesne, J., Edwards, J., Willis, A. E., Bushell, M., and Sansom, O. J.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Cancer Discovery
Publisher:American Association for Cancer Research
ISSN:2159-8274
ISSN (Online):2159-8290
Published Online:16 December 2020
Copyright Holders:Copyright © 2020 American Association for Cancer Research
First Published:First published in Cancer Discovery 11(5): 1228-1247
Publisher Policy:Reproduced in accordance with the publisher copyright policy

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
172879Examining the relationship between KRAS mutation and immunotherapy resistance in colorectal cancerOwen SansomMedical Research Council (MRC)MR/N021800/1CS - Beatson Institute for Cancer Research