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)

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: Pennel, Miss Kathryn and May-Wilson, Sebastian and Skalka, Dr George and Gilroy, Dr Kathryn and Leach, Dr Joshua and Faller, Dr William and Gay, David and Le Quesne, Professor John and McDonald, Dr Laura and Smith, Rachael and Edwards, Professor Joanne and Ridgway, Dr Rachel and Valeri, Dr Nicola and Sansom, Professor Owen and McKinnon, Dr Heather and Bushell, Professor Martin 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 > School of Cancer Sciences; College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• 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

Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
172879		Examining the relationship between KRAS mutation and immunotherapy resistance in colorectal cancer	Owen Sansom	Medical Research Council (MRC)	MR/N021800/1	CS - Beatson Institute for Cancer Research