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SUMMARY:Goldilocks and the two ERKs\; signalling in the ‘sweet spot’ u
 nderpins resistance to ERK pathway inhibitors - Simon Cook\, Signalling La
 boratory\, The Babraham Institute
DTSTART:20180914T133000Z
DTEND:20180914T143000Z
UID:TALK110239@talks.cam.ac.uk
CONTACT:Alessandro Esposito
DESCRIPTION: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 BRAFV60
 0E or KRASG13D which act to reinstate ERK1/2 signalling. \nHere we show th
 at BRAFV600E amplification and MEKi resistance are fully reversible follow
 ing drug withdrawal.  Resistant cells with BRAFV600E amplification become 
 addicted to MEKi to clamp ERK1/2 signalling at a level optimal for cell su
 rvival 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 inhib
 ited in mice that do not receive MEKi.  ERK1/2 hyperactivation (~20% activ
 e) following MEKi withdrawal drives expression of the cyclin-dependent kin
 ase inhibitor (CDKI) p57KIP2\, which promotes G1 cell cycle arrest and sen
 escence\, or expression of NOXA and cell death\; these ‘terminal’ resp
 onses select against those cells with amplified BRAFV600E.  ERK1/2-depende
 nt p57KIP2 expression is required for loss of BRAFV600E amplification and 
 determines the rate of reversal of MEKi resistance.  Thus\, BRAFV600E ampl
 ification confers a fitness deficit during drug withdrawal\, providing a r
 ationale for intermittent dosing (‘drug holidays’) to forestall resist
 ance.\nRemarkably\, MEKi resistance driven by KRASG13D amplification is no
 t reversible. ERK1/2 reactivation in the context of amplified KRASG13D doe
 s not inhibit proliferation but drives a ZEB1-dependent epithelial-to-mese
 nchymal transition that increases cell motility and promotes resistance to
  chemotherapy agents\, arguing strongly against the use of ‘drug holiday
 s’ in cases of resistance to MEKi driven by KRASG13D amplification.\n
LOCATION:Clifford Allbutt Lecture Theatre\, Clifford Allbutt Building (for
 mer LMB building)\, Addenbrooke's site
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