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Dr. Pierre Maisonneuve - New insights into RAF kinases regulation

Joint IPBS and CBI Seminar

Pierre Maisonneuve

Lunenfeld-Tanenbaum Research Institute, Toronto, Canada

New insights into RAF kinases regulation

RAF family kinases are a major driver of tumor formation. Their activation is dependent on dimerization of their kinase domains, which has emerged as a hindrance to drug development. The RAF family includes three kinase-active ARAF, BRAF, CRAF and two pseudokinase KSR1 and KSR2. RAF family members assemble into distinct homo- or heterodimers the biological relevance of which is newly emerging. However, the molecular mechanisms that dictate the formation of specific RAF dimers remain elusive.

The KSR pseudokinases have been described as scaffolds due to their apparent ability to bridge RAF isoforms and their substrate, MEK. Instead, we recently demonstrated that the pseudokinase KSR1 is an allosteric activator of BRAF and that KSR1 interaction with MEK regulates BRAF-KSR1 dimerization. Furthermore, by combining NMR and X-Ray crystallography, we have uncovered the molecular basis for the specific dimerization of BRAF with KSR1. Specifically, we identified a new domain in BRAF termed the BRS domain that specifically binds to the CC-SAM domain of KSR1 (1). These findings represent a paradigm shift in our understanding of how RAS/ERK signalling pathway functions.

Owing to the prevalence of BRAF kinase mutations in human cancer (8% of human cancer), great effort has been made to develop specific and potent inhibitors of BRAF. While FDA approved inhibitors of BRAF have shown tremendous efficacy in the clinic, the emergence of resistance mechanisms against these inhibitors inevidably leads to patients relapse. This highlights the demand for new strategies to inhibit BRAF function. With this perspective, we developed an innovative PROtealysis TArgeting Chimera (PROTAC) inducing BRAF degradation that displays improved potency relative to the conventional chemical inhibitor on which the PROTAC was derived (2). This study may open new avenues to target RAS-ERK inhibition in cancers.

 

Selected references

  1. Lavoie H*, Sahmi M*, Maisonneuve P* et al. MEK drives BRAF activation through allosteric control of KSR proteins. Nature 2018 Feb 22;554(7693):549-553
  2. Posternak G*, Tang X*, Maisonneuve P* et al. Functional characterization of a PROTAC directed against BRAFV600E. Nat Chem Biol 2020 In press

 

Contact: Olivier Neyrolles (Olivier.Neyrolles@ipbs.fr) & Fran├žois Cornet (Francois.Cornet@ibcg.biotoul.fr)

 

Due to the COVID-19-related situation, this seminar is restricted to IPBS and CBI members only.

 

Registration to attend the seminar on-line: click here

 

22 Sep

11:00 - 12:00

Fernand Gallais Conference room