Oncogenic KRAS rewires translation in colorectal cancer allowing targeting via the p38/MNK/eIF4E pathway


Year:

Session type:

Theme:

John Knight1,William Faller2,David Gay1,Nikola Vlahov1,Rachel Ridgway1,Christopher Proud3,Angel Nebreda4,Martin Bushell1,Anne Willis5,Owen Sansom1
1CRUK Beatson Institute,2NKI,3SAHMRI Adelaide,4IRB Barcelona,5MRC Toxicology Unit

Abstract

Background

KRAS mutation occurs in over 40% of colorectal cancers (CRC) and has recently become the defining mutation in the CMS3 sub-type of the human disease. However, targeting KRAS mutant tumours has proved difficult due to resistance against many therapeutic agents, including the licenced translation targeting rapalogues. Signalling downstream of KRAS is known to regulate protein synthesis, but the importance of this in CRC has not been explored.

Method

Using KRASG12D-driven genetically engineered mouse models (GEMMs), intestinal organoid culture, patient derived xenografts and advanced molecular biology techniques we unpick the role of KRAS mutation in the regulation of protein synthesis in CRC.

Results

In the mouse intestine KRASG12D drives rapid tumorigenesis, increased protein synthesis and a resistance to rapamycin treatment akin to clinical observations. We find that rapamycin suppresses protein synthesis in our KRAS-driven models, despite tumour resistance to rapamycin for proliferation. Unexpectedly we find that translation is actively suppressed in the transformed mouse intestine, with evidence to suggest this avoids the induction of the integrated stress response. From GEMMs and patient derived xenografts we identify upregulation of the p38/MNK/eIF4E pathway downstream of oncogenic KRAS. Targeting this pathway in the mouse with genetic knockouts or using small molecules significantly reduces proliferation and extends survival almost 10-fold, but only in combination with rapamycin. We find that eIF4E phosphorylation is required for expression of proliferative mRNAs such as c-Myc and cyclin D1, the protein expression of which is further reduced by combination with rapamycin.

Conclusion

KRAS mutation rewires the regulation of translation in CRC, tuning protein synthesis to a level for maximal protein output without inducing stress. This also generates a translational reserve, which allows resistance to translation suppression. However, p38/MNK/eIF4E mediated selective mRNA translation is essential for proliferation following suppression of protein synthesis and can be targeted to suppress tumour proliferation.