IVORIaN · RAS/C-RAF interaction: A new pharmacological target in Kras-driven lung cancer.
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2017-06-01 → 2019-05-31
- EU contribution
- €183,455
- Participants
- 1
- Scheme
- MSCA-IF-EF-ST
Lines connect the coordinator with its partners.
Results in brief
RAS/C-RAF interaction: A new pharmacological target in Kras-driven lung cancer.
Lung cancer is the leading cause of cancer-related deaths worldwide, accounting for an estimated 2 million new cases per year in 2018 (https://www.wcrf.org/dietandcancer/cancer-trends/lung-cancer-statistics). 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.
Data: CORDIS, © European Union
Project objective
Lung adenocarcinoma is the most frequent subtype of lung cancer and patients harbour activating mutations in the KRAS gene in approximately 25% of the cases. Unfortunately, regardless of the outcome of recent studies identifying specific KRASG12C inhibitors, so far, oncogenic KRAS is not a druggable target yet. The best-characterized KRAS effector pathway, the ERK cascade consists of RAF, MEK and ERK proteins that can be inhibited with small molecules targeting their kinase activities. As the development of RAF and MEK kinases inhibitors progressed, feedback loop reactivating the ERK cascade have emerged, inducing resistance to treatment. Thus, new innovative strategies are needed to achieve a more long-term inhibition of this signalling pathway, while reducing detrimental side effects due to MAPK inhibition in normal cells. It has been described more than 20 years ago that RAF directly interacts with RAS through its Ras Binding Domain (RBD), and many research groups have been trying to disrupt this interaction developing allosteric inhibitors as a cancer therapy. At the moment, those molecules need to be improved in order to achieve a strong inhibition of this pathway. Surprisingly, no mouse model actually demonstrates the requirement of RAS/RAF interaction during KRAS-induced lung tumourigenesis. Here, we propose to investigate this crucial question using a new mouse model allowing us to conditionally disrupt RAS/RAF interaction in vivo. Using the leading mouse model to study lung cancer (LSL-KrasG12D/+; p53-/- mice), we will take advantage of both Cre/LoxP and FLIPo/Frt technologies to investigate the role of RAS/RAF interaction during lung tumours maintenance, as well as its function in tumour/host crosstalk and normal physiology. All together, these investigations will provide important insights into the clinical relevance of developing RAS interaction inhibitors for the treatment of RAS-driven tumours.
Original text from CORDIS.
Participants
- THE FRANCIS CRICK INSTITUTE LIMITED · LondonCoordinatorUnited Kingdom
Links
Data: CORDIS, © European Union