title: Tumor cells with KRAS or BRAF mutations or ERK5/MAPK7 amplification are not addicted to ERK5 activity for cell proliferation.
abstract: ERK5, encoded by MAPK7, has been proposed to play a role in cell proliferation, thus attracting interest as a cancer therapeutic target. While oncogenic RAS or BRAF cause sustained activation of the MEK1/2-ERK1/2 pathway, ERK5 is directly activated by MEK5. It has been proposed that RAS and RAF proteins can also promote ERK5 activation. Here we investigated the interplay between RAS-RAF-MEK-ERK and ERK5 signaling and studied the role of ERK5 in tumor cell proliferation in 2 disease-relevant cell models. We demonstrate that although an inducible form of CRAF (CRAF:ER*) can activate ERK5 in fibroblasts, the response is delayed and reflects feed-forward signaling. Additionally, oncogenic KRAS and BRAF do not activate ERK5 in epithelial cells. Although KRAS and BRAF do not couple directly to MEK5-ERK5, ERK5 signaling might still be permissive for proliferation. However, neither the selective MEK5 inhibitor BIX02189 or ERK5 siRNA inhibited proliferation of colorectal cancer cells harbouring KRAS(G12C/G13D) or BRAF(V600E). Furthermore, there was no additive or synergistic effect observed when BIX02189 was combined with the MEK1/2 inhibitor Selumetinib (AZD6244), suggesting that ERK5 was neither required for proliferation nor a driver of innate resistance to MEK1/2 inhibitors. Finally, even cancer cells with MAPK7 amplification were resistant to BIX02189 and ERK5 siRNA, showing that ERK5 amplification does not confer addiction to ERK5 for cell proliferation. Thus ERK5 signaling is unlikely to play a role in tumor cell proliferation downstream of KRAS or BRAF or in tumor cells with ERK5 amplification. These results have important implications for the role of ERK5 as an anti-cancer drug target.
authors.affiliation: a Signalling Laboratory; The Babraham Institute ; Cambridge , UK.
authors.forename: Pamela A
authors.initials: PA
authors.lastname: Lochhead
authors.affiliation: b Biological Chemistry Facility; The Babraham Institute ; Cambridge , UK.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Clark
authors.affiliation: c The Northern Institute for Cancer Research; University of Newcastle upon Tyne , Newcastle , UK.
authors.forename: Lan-Zhen
authors.initials: LZ
authors.lastname: Wang
authors.affiliation: d Cancer Research Technology; The Beatson Institute for Cancer Research; Garscube Estate ; Glasgow , UK.|e Current address: Translational Radiation Biology; The Beatson Institute for Cancer Research; Garscube Estate ; Glasgow , UK.
authors.forename: Lesley
authors.initials: L
authors.lastname: Gilmour
authors.affiliation: a Signalling Laboratory; The Babraham Institute ; Cambridge , UK.|f Current address: Novartis ; Basel , Switzerland.
authors.forename: Matthew
authors.initials: M
authors.lastname: Squires
authors.affiliation: a Signalling Laboratory; The Babraham Institute ; Cambridge , UK.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Gilley
authors.affiliation: g Cancer Research Technology; CRT Discovery Laboratories; London Bioscience Innovation Centre ; London , UK.|h Current address: Centre for Drug Development ; Cancer Research UK ; London , UK.
authors.forename: Caroline
authors.initials: C
authors.lastname: Foxton
authors.affiliation: c The Northern Institute for Cancer Research; University of Newcastle upon Tyne , Newcastle , UK.
authors.forename: David R
authors.initials: DR
authors.lastname: Newell
authors.affiliation: c The Northern Institute for Cancer Research; University of Newcastle upon Tyne , Newcastle , UK.
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Wedge
authors.affiliation: a Signalling Laboratory; The Babraham Institute ; Cambridge , UK.
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Cook
mesh_terms: D000814:Aniline Compounds / Q000008:administration & dosage; D001562:Benzimidazoles / Q000008:administration & dosage; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D006801:Humans; D007211:Indoles / Q000008:administration & dosage; D048054:Mitogen-Activated Protein Kinase 7 / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects
chemical_list: C517975:AZD 6244; D000814:Aniline Compounds; C533207:BIX 02189; D001562:Benzimidazoles; D007211:Indoles; C117307:KRAS protein, human; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; C481581:MAPK7 protein, human; D048054:Mitogen-Activated Protein Kinase 7; D016283:Proto-Oncogene Proteins p21(ras)
keywords: BIX02189; ERK5; MEK5; RAF; RAS; selumetinib; tumor cell proliferation