A seminar hosted by the School of Cellular and Molecular Medicine

Abstract: The RAS-regulated RAF-MEK-ERK1/2 signalling pathway is frequently de-regulated in cancer due to driving, mutations in RAS, BRAF, CRAF, MEK1 and MEK2. Drug discovery efforts have seen the development and clinical approval of inhibitors of BRAF (RAFi), MEK1/2 (MEKi) and most recently KRASG12C that are transforming the treatment of certain types of melanoma, colorectal cancer and non-small cell lung cancer.

Whilst RAFi successfully target tumours with BRAFV600E/K mutations, they have failed in tumours with wild type RAF, due to RAFi driving paradoxical activation of RAF dimers and activation of ERK1/2. We have found that a range of RAFi drive paradoxical RAF activation and cell cycle arrest. We anticipated that this reflected hyperactivation of ERK1/2 outside of the sweet-spot that maintains proliferation. However, the G1 cell cycle arrest is independent of ERK1/2. We have now found that RAFi drive activation of an ancient, evolutionarily conserved stress signalling pathway that normally promotes cell survival and are investigating the underlying mechanism for this.

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