University of Cambridge > Talks.cam > ae275's list > Goldilocks and the two ERKs; signalling in the ‘sweet spot’ underpins resistance to ERK pathway inhibitors

Goldilocks and the two ERKs; signalling in the ‘sweet spot’ underpins resistance to ERK pathway inhibitors

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Tumour cells with BRAF or RAS mutations are ‘addicted’ to ERK1 /2 signalling for proliferation and RAFi and/or MEKi are now approved for use in the clinic. However, despite some striking clinical responses, resistance emerges within 9-12 months resulting in disease progression. Acquired resistance to MEKi often occurs through amplification of BRAFV600E or KRASG13D which act to reinstate ERK1 /2 signalling. Here we show that BRAFV600E amplification and MEKi resistance are fully reversible following drug withdrawal. Resistant cells with BRAFV600E amplification become addicted to MEKi to clamp ERK1 /2 signalling at a level optimal for cell survival and proliferation (2-3% of total ERK1 /2 active, quantified by mass spectrometry). This is seen in cell culture and in vivo where growth of resistant cells with BRAFV600E amplification as tumour xenografts is inhibited in mice that do not receive MEKi. ERK1 /2 hyperactivation (~20% active) following MEKi withdrawal drives expression of the cyclin-dependent kinase inhibitor (CDKI) p57KIP2, which promotes G1 cell cycle arrest and senescence, or expression of NOXA and cell death; these ‘terminal’ responses select against those cells with amplified BRAFV600E . ERK1 /2-dependent p57KIP2 expression is required for loss of BRAFV600E amplification and determines the rate of reversal of MEKi resistance. Thus, BRAFV600E amplification confers a fitness deficit during drug withdrawal, providing a rationale for intermittent dosing (‘drug holidays’) to forestall resistance. Remarkably, MEKi resistance driven by KRASG13D amplification is not reversible. ERK1 /2 reactivation in the context of amplified KRASG13D does not inhibit proliferation but drives a ZEB1 -dependent epithelial-to-mesenchymal transition that increases cell motility and promotes resistance to chemotherapy agents, arguing strongly against the use of ‘drug holidays’ in cases of resistance to MEKi driven by KRASG13D amplification.

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