title: Tumour cell responses to MEK1/2 inhibitors: acquired resistance and pathway remodelling.
abstract: 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.
authors.affiliation: Laboratory of Signalling and Cell Fate, The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK.
authors.forename: Annette S
authors.initials: AS
authors.lastname: Little
authors.forename: Kathryn
authors.initials: K
authors.lastname: Balmanno
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Sale
authors.forename: Paul D
authors.initials: PD
authors.lastname: Smith
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Cook
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology*; D045744:Cell Line, Tumor; D029721:Drosophila Proteins; D019008:Drug Resistance, Neoplasm; D005784:Gene Amplification; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C517975:AZD 6244; D000970:Antineoplastic Agents; D001562:Benzimidazoles; D029721:Drosophila Proteins; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; C113875:msn protein, Drosophila; C482119:BRAF protein, human; D017346:Protein Serine-Threonine Kinases; D048493:Proto-Oncogene Proteins B-raf; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins