The Raf/MEK1/2 [mitogen-activated protein kinase/ERK (extracellular-signal-regulated kinase) kinase 1/2]/ERK1/2 signalling pathway is frequently activated in human tumours due to mutations in BRAF or KRAS. B-Raf and MEK1/2 inhibitors are currently undergoing clinical evaluation, but their ultimate success is likely to be limited by acquired drug resistance. We have used colorectal cancer cell lines harbouring mutations in B-Raf or K-Ras to model acquired resistance to the MEK1/2 inhibitor selumetinib (AZD6244). Selumetinib-resistant cells were refractory to other MEK1/2 inhibitors in cell proliferation assays and exhibited a marked increase in MEK1/2 and ERK1/2 activity and cyclin D1 abundance when assessed in the absence of inhibitor. This was driven by a common mechanism in which resistant cells exhibited an intrachromosomal amplification of their respective driving oncogene, B-Raf V600E or K-RasG13D. Despite the increased signal flux from Raf to MEK1/2, resistant cells maintained in drug actually exhibited the same level of ERK1/2 activity as parental cells, indicating that the pathway is remodelled by feedback controls to reinstate the normal level of ERK1/2 signalling that is required and sufficient to maintain proliferation in these cells. These results provide important new insights into how tumour cells adapt to new therapeutics and highlight the importance of homoeostatic control mechanisms in the Raf/MEK1/2/ERK1/2 signalling cascade.
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February 2012
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Conference Article|
January 19 2012
Tumour cell responses to MEK1/2 inhibitors: acquired resistance and pathway remodelling
Annette S. Little;
Annette S. Little
*Laboratory of Signalling and Cell Fate, The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, U.K.
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Kathryn Balmanno;
Kathryn Balmanno
*Laboratory of Signalling and Cell Fate, The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, U.K.
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Matthew J. Sale;
Matthew J. Sale
*Laboratory of Signalling and Cell Fate, The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, U.K.
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Paul D. Smith;
Paul D. Smith
†iMED Oncology, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, U.K.
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Simon J. Cook
Simon J. Cook
1
*Laboratory of Signalling and Cell Fate, The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, U.K.
1To whom correspondence should be addressed (email simon.cook@bbsrc.ac.uk).
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Publisher: Portland Press Ltd
Received:
July 14 2011
Online ISSN: 1470-8752
Print ISSN: 0300-5127
© The Authors Journal compilation © 2012 Biochemical Society
2012
Biochem Soc Trans (2012) 40 (1): 73–78.
Article history
Received:
July 14 2011
Citation
Annette S. Little, Kathryn Balmanno, Matthew J. Sale, Paul D. Smith, Simon J. Cook; Tumour cell responses to MEK1/2 inhibitors: acquired resistance and pathway remodelling. Biochem Soc Trans 1 February 2012; 40 (1): 73–78. doi: https://doi.org/10.1042/BST20110647
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