Case Study 3: Targeting translational control for cancer therapy

Summary

• Activation of the mTOR and KRAS oncogene signalling pathways leads to reprogramming of the translational apparatus in vivo

• Targeting these downstream translation components genetically or with therapeutic agents suppresses colorectal tumour formation

1) APC mutation results in increased translation elongation, which can be blocked by rapamycin. 2) Addition of oncogenic KRAS mutation activates MNK and eIF4E, stimulating translation and conferring resistance to rapamycin. 3) Dual inhibition of MNK and mTOR results in suppression of tumour development. 4) Identification of these and other important targets has contributed to the formation of the mRNA Translational Alliance for therapeutic development, which is made up of a PI team for driving basic science and CRUK Therapeutic Innovation for drug discovery funded by BMS (2017-2022).

Delivery of oncogenic gene expression programmes is achieved by reprogramming of the translation apparatus downstream of specific signalling pathway activation. The altered gene expression programmes enabled by these processes are required for tumourigenesis, and genetic or therapeutic intervention in these can suppress tumour development. Our new understanding of the role that translational control plays in tumour development is allowing us to develop novel approaches to therapeutically target this process.

Tumourigenesis is the result of altered gene expression programmes across multiple cell types, achieved by natural selection in the malignant clones and by responses to these aberrant cells by host tissues. The protein synthesis apparatus is highly regulated, influencing protein synthesis for orchestration of normal gene programmes, and in malignant cells, for the establishment of highly abnormal proteomes that support oncogenesis. Previously, the Sansom and Bushell labs have collaboratively shown that, when the main gene mutated in patients with CRC, Adenomatous polyposis coli (APC), is deleted in mouse models it controls translation via the mTOR pathway, and importantly that rapamycin suppresses tumour formation in these mouse models (1). This work has led to clinical trials with an mTOR inhibitor in patients with familial adenomatous polyposis (FAP), who are predisposed to adenoma formation due to germline mutation in the APC gene. These trials confirmed that mTOR inhibition resulted in suppression of colonic polyps in patients, validating this approach (2).

Although mutation of the APC gene is a founder event in early tumourigenesis, by the time that patients with CRC present in the clinic their tumours often have multiple additional mutations. KRAS is the second most frequently mutated gene in CRC often co-occurring with APC loss. Complex mouse models that carry an activating oncogenic mutation in KRAS in addition to deletion of APC, develop tumours that are resistant to mTOR inhibition. Further investigation revealed that rewiring of signalling pathway cascades leading to additional alterations to the translational apparatus is responsible for this resistance to mTOR inhibition. Specifically, mutant KRAS signals to eIF4E – a key component of the translation initiation machinery. KRAS signalling to eIF4E, in turn, leads to an activating phosphorylation of eIF4E by the kinase MNK. This phosphorylation site is close to the cap binding region on eIF4E and results in recruitment of distinct mRNAs to the ribosome. Importantly, these insights enabled us to define a mechanism for re-sensitisation to mTOR inhibitors, by dual targeting alongside the MNK kinase. Indeed, a combination of mTOR inhibition and selective targeting of the MNK suppressed tumour development through the specific regulation of oncogenic mRNA targets (3). Discussions are ongoing with eFFECTOR Therapeutics, who have developed a drug that blocks signalling to eIF4E with the goal of setting up preclinical trials for dual targeting with mTOR inhibitors.

These observations coupled with other critical findings indicate a complete reliance on dysregulation of translational control for cancer development, and this has led to the establishment of the mRNA Translation Alliance in conjunction with Cancer Research Horizons (CRH) and Bristol Myers Squibb (BMS). This alliance is a five-year (2017-2022) consortium to prosecute the development of chemical matter to target the protein synthesis apparatus. Within the CRUK Beatson Institute, we now have a large collective team working intensely on mRNA regulation, including the Bushell, Le Quesne, Sansom, Cowling, Norman and Miller groups; three of which (Sansom, Bushell, Le Quesne) are the principal investigators involved in the Alliance. The interaction between the cancer biology laboratories and the drug discovery groups, partially situated at the Institute, is key to the collaborative alliance network. Close physical proximity has allowed rapid transfer of reagents and methods between the research and drug discovery laboratories, which greatly enhances progress. Over the last five years, the Alliance has developed an advanced portfolio within this area and has developed chemical matter against several mRNA translational control targets. Successful alignment of these therapeutic reagents to patient groups who are likely to benefit from their use is key to our strategy, and with our extensive patient tissue cohorts and diverse preclinical models we can link these novel therapeutics to patient populations very early in the drug discovery process.

References

1. Faller WJ et al. mTORC1-mediated translational elongation limits intestinal tumour initiation and growth. Nature. 2015; 517: 497-500
2. Yuksekkaya H et al. Familial adenomatous polyposis; succesful use of sirolimus. Am J Gastroenterol. 2016; 111: 1040-1
3. Knight JRP et al. MNK inhibition sensitizes KRAS-mutant colorectal cancer to mTORC1 inhibition by reducing eIF4E phosphorylation and c-MYC expression. Cancer Discov. 2021; 11: 1228-47