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.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | Cancer Discovery |
| Vol/bind | 11 |
| Udgave nummer | 5 |
| Sider (fra-til) | 1228-1247 |
| Antal sider | 20 |
| ISSN | 2159-8274 |
| DOI | |
| Status | Udgivet - 2021 |
| Udgivet eksternt | Ja |
Bibliografisk note
Funding Information:C. Alexandrou reports grants from Cancer Research Technology Limited (a wholly owned subsidiary of Cancer Research UK) during the conduct of the study. G. Kanellos reports grants from Cancer Research Technology Limited (a wholly owned subsidiary of Cancer Research UK) during the conduct of the study. C. MacKay reports grants from Cancer Research Technology Limited (a wholly owned subsidiary of Cancer Research UK) during the conduct of the study; grants from Cancer Research Technology Limited (a wholly owned subsidiary of Cancer Research UK) outside the submitted work. A. Cheasty reports other support from Cancer Research Technology Limited (CRT) during the conduct of the study; other support from Cancer Research Technology Limited (CRT) outside the submitted work. E. Stanway reports other support from Cancer Research Technology (CRT) during the conduct of the study; other support from Cancer Research Technology (CRT) outside the submitted work. N. Valeri reports personal fees from Bayer, Eli Lilly, and Pfizer, and other support from Menarini BioSystem outside the submitted work. N. Sonenberg reports serving on the SAB of Effector Pharmaceuticals who provided the drug eFT508. N. Sonenberg is a minor stockholder of Effector Pharmaceuticals. C.G. Proud reports a patent for MNK inhibitors pending. N.P. Jones reports other support from BMS/Celgene during the conduct of the study; other support from BMS/Celgene outside the submitted work; and received indirect funds from BMS/ Celgene given to Cancer Research Technology (CRT), a wholly owned subsidiary of Cancer Research UK, to work on mRNA translation. M.E. Swarbrick reports other support from Cancer Research Technology Ltd. (CRT) during the conduct of the study; other support from Cancer Research Technology Ltd. (CRT) outside the submitted work. H.J. McKinnon reports grants from CRUK Research Technology during the conduct of the study. M. Bushell reports being part of Cancer Research Technology mRNA translation alliance, which is engaged in drug discovery activity targeting the translational apparatus. O.J. Sansom reports grants from Cancer Research Technology (a wholly own subsidiary of CRUK) during the conduct of the study; grants from Novartis and AstraZeneca outside the submitted work. No other disclosures were reported.
Funding Information:
Funding for the Sansom laboratory was from CRUK (A17196, A24388, and A21139), The European Research Council ColonCan (311301), a Wellcome Trust Collaborative Award in Science (201487), and a CRUK Grand Challenges (A25045 and A29055). J.D. Leach was supported by an MRC Clinical Research Predoctoral Training Fellowship (MR/N021800/1). K. Pennel was supported by an MRC Fellowship (MR/R502327/1). The authors are grateful to the Core Services and Advanced Technologies at the CRUK Beatson Institute (C596/A17196), particularly the Histology Services, Transgenic Technology Laboratory, Molecular Technologies, and Biological Services Unit. We thank Michael Pollak from McGill University for critical reading of the manuscript.
Funding Information:
for the Sansom laboratory was from CRUK (A17196, A24388, and A21139), The European Research Council ColonCan (311301), a Wellcome Trust Collaborative Award in Science (201487), and a CRUK Grand Challenges (A25045 and A29055). J.D. Leach was supported by an MRC Clinical Research Predoctoral Training Fellowship (MR/N021800/1). K. Pennel was supported by an MRC Fellowship (MR/R502327/1). The authors are grateful to the Core Services and Advanced Technologies at the CRUK Beatson Institute (C596/A17196), particularly the Histology Services, Transgenic Technology Laboratory, Molecular Technologies, and Biological Services Unit. We thank Michael Pollak from McGill University for critical reading of the manuscript.
Publisher Copyright:
© 2020 American Association for Cancer Research.