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RAS/C-RAF interaction: A new pharmacological target in Kras-driven lung cancer.

Periodic Reporting for period 1 - IVORIaN (RAS/C-RAF interaction: A new pharmacological target in Kras-driven lung cancer.)

Reporting period: 2017-06-01 to 2019-05-31

Lung cancer is the leading cause of cancer-related deaths worldwide, accounting for an estimated 2 million new cases per year in 2018 ( The most frequent mutations found in patients occur in genes encoding for the KRAS oncoprotein (33% - smoking related).

Currently, no specific treatments are available for these patients carrying a KRAS mutation. As the KRAS oncoprotein is involved in many cellular processes, it is extremely important to understand how it works, and what are the functions of its downstream effectors. Identifying and characterising new therapeutic targets allows for the design of new potent drugs with the potential of increasing patients survival. The CRAF kinase is a well described downstream effector of KRAS and a very attractive therapeutic target. Indeed, ablation of the protein in a mouse model of KRAS-driven lung cancer (similar to what happens in the patient) triggers tumour regression, with no apparent long term toxicity. However, although complete removal of a protein provides an excellent proof of concept of a new therapeutic target, it is hardly applicable for therapy.

As a direct interaction with KRAS is required for CRAF activation, this project aims to demonstrates, using sophisticated mouse models of lung cancer, that disrupting the interaction between the two proteins, would mimic the effects observed when depleting the pool of protein. This approach aims to demonstrate that a hypothetical drug targeting KRAS/CRAF interaction could improve the survival of patients diagnosed with KRAS-mutant lung adenocarcinoma.
In order to demonstrate that targeting RAS/CRAF protein-protein interaction would be a good therapeutic target for KRAS-driven lung cancer, we engineered a new mouse model in which the CRAF protein cannot interact with KRAS anymore.

To achieve this goal, we took advantage of the CRISPR/Cas9 technology and introduced a single point mutation in the murine CRAF gene. As expected, this single mutation completely abrogates CRAF interaction with KRAS. Moreover, expression of the CRAF mutant in the adult mouse does not induce any long term toxicity. This further suggest that targeting KRAS/CRAF interaction with a drug would not trigger major adverse effects in patients. We also engineered and established lung cancer cell lines with the same mutation and used them to understand which cellular mechanisms are impaired upon disruption of the interaction. As expected, we can show that those cells have an impaired tumour formation potential in vivo, validating the therapeutic potential of targeting this specific protein-protein interaction. As a courtesy of the MSCA fellowship, I had the opportunity to present this work at multiple international conferences.

The project attracted a lot of interest and enthusiasm from scientists working in the field and beyond, as well as from pharmaceutical companies.
At the end of the project, we aim to demonstrate that targeting CRAF/RAS protein interaction will trigger tumour regression, in a mouse model of KRAS-driven lung adenocarcinoma that recapitulated the human disease.

In addition, we are elucidating the molecular mechanism behind it using our in vitro cell line model. Many research labs around the world tried to develop peptides or small molecules to disrupt this particular interaction, but none of them are currently potent enough to be taken into clinical trials. The interaction between RAS and CRAF is extremely challenging to disrupt. With no formal demonstration of its therapeutic potential as of yet, research efforts into drug development in this context have been abandoned, at the cost of patient welfare.We developed a new mouse model that genetically mimics a drug treatment in vivo, providing a clear demonstration of a therapeutic benefit.

We are confident that our work will rekindle interest in this field and encourage both academia and industry to focus on identifying new potent drugs tarting this interaction. The ultimate goal of the project is to provide a new therapy targeting CRAF/KRAS interaction to tackle KRAS-driven lung cancer and improve patient lives.
Potential new drug targeting RAS/CRAF interaction