| Autor: |
John R P, Knight, Constantinos, Alexandrou, George L, Skalka, Nikola, Vlahov, Kathryn, Pennel, Leah, Officer, Ana, Teodosio, Georgios, Kanellos, David M, Gay, Sebastian, May-Wilson, Ewan M, Smith, Arafath K, Najumudeen, Kathryn, Gilroy, Rachel A, Ridgway, Dustin J, Flanagan, Rachael C L, Smith, Laura, McDonald, Craig, MacKay, Anne, Cheasty, Kerri, McArthur, Emma, Stanway, Joshua D, Leach, Rene, Jackstadt, Joseph A, Waldron, Andrew D, Campbell, Georgios, Vlachogiannis, Nicola, Valeri, Kevin M, Haigis, Nahum, Sonenberg, Christopher G, Proud, Neil P, Jones, Martin E, Swarbrick, Heather J, McKinnon, William J, Faller, John, Le Quesne, Joanne, Edwards, Anne E, Willis, Martin, Bushell, Owen J, Sansom |
| Rok vydání: |
2020 |
| Předmět: |
|
| Zdroj: |
Cancer Discov |
| ISSN: |
2159-8290 |
| Popis: |
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 KRAS(G12D) 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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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