The research team led by Professor Marc Therrien, Scientific Director of the IRIC and Principal Investigator at the Institute just published an article in the prestigious scientific journal Nature Communications, regarding the mechanisms of activation of the oncoprotein RAF.
The new data obtained by the IRIC researchers on this important cellular regulator will help guide the development of a new generation of drugs against a wide range of cancers.
Cell signaling and cancer
Cell behavior is largely controlled by signals coming from their environment inside our body. To send a message to the cell, the signal (hormones, neurotransmitters, growth factors, etc.) must be transmitted by a chain of several proteins within the cell, known as a signalling pathway. It’s like a relay race in which the finish line is often the nucleus, namely the cell’s control center.
In the case of the RAS/MAPK signaling pathway, the RAS protein located in the cell membrane is one of the first elements of the chain, while MAPK acts much more downstream. This signaling pathway is particularly important because in 25%-30% of all cancers (and up to 90% in the case of pancreatic cancer), mutations lead to its continuous activation. An erroneous message is then sent to the cell which, in some instances, leads to a disorderly proliferation. It’s an essential aspect of tumor formation.
Professor Therrien and his team, have been working for several years to try to understand the molecular mechanisms of RAS/MAPK signaling. Greater understanding of these mechanisms could lead to new strategies for preventing the survival and proliferation of cancer cells.
RAF activation and inhibition
A promising approach is to target the RAF protein, a crucial intermediary in cell signal transmission. Because of its preponderant role in tumor formation, pharmaceutical companies have invested considerable effort to identify molecules that inhibit RAF enzymatic activity. Although there has been some clinical success, it turns out that on the whole these inhibitors have the unfortunate habit of stimulating the growth of cancer cells instead of reducing it; a paradox that has puzzled an entire community of investigators and clinicians.
IRIC investigators recently discovered new elements to explain this paradox by showing how RAF activation requires three interconnected events involving RAF and RAS and how the drugs currently available unexpectedly stimulate some of those interactions. This new understanding at the molecular level results in being able to propose characteristics that the new generation of RAF inhibitors must possess to constitute effective cancer drugs. Ideally, these new synthetic molecules should stabilize a closed conformation of the RAF protein to prevent productive contact with RAS, as well as block the creation of contact between two RAF proteins, which usually stimulates their capacity to activate the signaling chain downstream.
Thanks to this new recently acquired knowledge, Professor Therrien’s research group and the IRIC’s team of medicinal chemists under the leadership of Professor Anne Marinier, are already on the trail of this new generation of cancer drugs.
To read the full article, visit: http://www.nature.com/articles/s41467-017-01274-0
RAF inhibitors promote RAS-RAF interaction by allosterically disrupting RAF autoinhibition
Ting Jin, Hugo Lavoie, Malha Sahmi, Maud David, Christine Hilt, Amy Hammell, Marc Therrien