GPMDB00215OtherVogel CJ, et al.InstrumentNot AvailableNot availableHomo_sapiens_viruses, Human25728708A.J.R.Heck@uu.nlhttp://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320014060http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320014061http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320014062http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320014016http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320014017http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320014018http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320014019http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320014052http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320014053http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320014054http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320014010http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320014055http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320014011http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320014012http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320014056http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320014013http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320014057http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320014058http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320014014http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320014059http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320014027http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320014028http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320014029http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320013979http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320014063http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320014020http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320014021http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320014022http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320014023http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320014024http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320014025http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320014026http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320014040http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320014038http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320013983http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320013984http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320014039http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320013985http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320013986http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320013987http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320013988http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320013989http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320014030http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320014031http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320014032http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320014033http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320014034http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320014035http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320013980http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320014036http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320013981http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320014037http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320013982http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320014050http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320014051http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320013994http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320014049http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320014005http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320014006http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320013995http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320013996http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320014007http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320013997http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320014008http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320014009http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320013998http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320013999http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320014041http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320014042http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320014043http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320014044http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320014000http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320014001http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320014045http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320013990http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320013991http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320014046http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320014002http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320014003http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320013992http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320014047http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320014004http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320014048http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320013993Division of Molecular Oncology, The Netherlands Cancer InstituteNot availableGPMDBNo effective targeted therapy is currently available for NRAS mutant melanoma. Experimental MEK inhibition is rather toxic and has only limited efficacy in clinical trials. At least in part, this is caused by the emergence of drug resistance, which is commonly seen for single agent treatment and shortens clinical responses. Therefore, there is a dire need to identify effective companion drug targets for NRAS mutant melanoma. Here, we show that at concentrations where single drugs had little effect, ROCK inhibitors GSK269962A or Fasudil, in combination with either MEK inhibitor GSK1120212 (Trametinib) or ERK inhibitor SCH772984 cooperatively caused proliferation inhibition and cell death in vitro. Simultaneous inhibition of MEK and ROCK caused induction of BimEL , PARP, and Puma, and hence apoptosis. In vivo, MEK and ROCK inhibition suppressed growth of established tumors. Our findings warrant clinical investigation of the effectiveness of combinatorial targeting of MAPK/ERK and ROCK in NRAS mutant melanoma.Cooperative induction of apoptosis in NRAS mutant melanoma by inhibition of MEK and ROCK.Vogel Celia J CJ,Smit Marjon A MA,Maddalo Gianluca G,Possik Patricia A PA,Sparidans Rolf W RW,van der Burg Sjoerd H SH,Verdegaal Els M EM,Heck Albert J R AJ,Samatar Ahmed A AA,Beijnen Jos H JH,Altelaar A F Maarten AF,Peeper Daniel S DS,Vogel Celia J CJ, Smit Marjon A MA, Maddalo Gianluca G, Possik Patricia A PA, Sparidans Rolf W RW, van der Burg Sjoerd H SH, Verdegaal Els M EM, Heck Albert J R AJ, Samatar Ahmed A AA, Beijnen Jos H JH, Altelaar A F Maarten AF, Peeper Daniel S DScellular suicide, MAPKK7, cell suicide, SAPKK4, NRAS1, apoptotic cell death, caspase-dependent programmed cell death, NS6, malignant melanoma NOS (morphologic abnormality), Malignant Melanomas, apoptotic programmed cell death, type I programmed cell death, PRKMK7, Malignant, activation of apoptosis, MM - Malignant melanoma, Melanomas, signaling (initiator) caspase activity, Melanoma, induction of apoptosis, Malignant Melanoma, CMNS, ALPS4, Malignant melanoma (morphologic abnormality), MEK, Mek, NOS, malignant melanoma (disorder), Melanosarcoma, JNKK2, morphology (morphologic abnormality), NCMS, apoptosis signaling, N-ras, apoptosis, MKK7, Naevocarcinoma, MK., SAPKK-4, Malignant melanoma, MEK 7, apoptosis activator activity, no ICD-O subtype, induction of apoptosis by p53, [M]Malignant melanoma NOS (morphologic abnormality), no ICD-O subtype (morphologic abnormality), apoptotic program, [M]Malignant melanoma NOS, commitment to apoptosis, programmed cell death by apoptosis, AV095280MAPKK7, extracellular signal-regulated kinase activity, pp44mapk, JTP-74057, chromatophore, experimental, GSK-269962A, JTP74057, 4-Diazepine, Tyro5, 1H-1, chromatocyte, Mpk2, NS6, drug susceptibility/resistance, malignant melanoma NOS (morphologic abnormality), p42mapk, PRKMK7, Malignant, Hek5, AA407128, LeMPK3, GSK 269962A, JTP 74057, p44mpk, ALPS4, Malignant melanoma (morphologic abnormality), AT 877, Prkm1, Dp38, malignant melanoma (disorder), mitogen-activated protein kinase activity, Melanosarcoma, p42-MAPK, JNKK2, SAPK2, drug resistance, NCMS, ERK, PRKM1, treatment, PRKM2, N-ras, methods, accidental cell death., pp42, experimental section, MKK7, EK5, Naevocarcinoma, PCBC, MEK 7, p42 mitogen-activated protein kinase activity, ATP:protein phosphotransferase (MAPKK-activated) activity, MP kinase activity, drugs, [M]Malignant melanoma NOS (morphologic abnormality), no ICD-O subtype (morphologic abnormality), medicine, Concentration, Concentrations, [M]Malignant melanoma NOS, disease management, MBP kinase II activity, necrosis, STK26, p38-2, myelin basic protein kinase activity, GSK 1120212, GSK269962A, HA 1077, data, MAP kinase 2 activity, DRT, SAPKK4, NRAS1, drug, ERK-2, ERK1, MAP-2 kinase activity, ERK2, Erk2, Malignant Melanomas, PMK-2, PMK-1, Cell, MK, PMK-3, MM - Malignant melanoma, p38delta, GSK-1120212, Melanomas, Experiment, Melanoma, p41mapk, MAPK, Malignant Melanoma, HA-1077, CMNS, Resistance, MBP kinase I activity, MEK, Mek, NOS, hexahydro-1-(5-isoquinolinylsulfonyl)-, fasudil mesylate, Death, morphology (morphologic abnormality), AT877, pigment cell, mitogen activated kinase activity, P42MAPK, CAPB, SAPKK-4, p38, pigment cells, Malignant melanoma, MAPK2, AT-877, experimental procedures, C78273, Drug, pigments, AU018647, no ICD-O subtype, ERT1, p41, p40, EPHT3, fasudil hydrochloride, biological pigment, pigmentation, 1-(5-isoquinolinesulfonyl)homopiperazine, AV095280, GSK1120212, Attentions, 9030612K14Rik, MAP kinase 1 activitycellular suicide, MAPKK7, cell suicide, SAPKK4, NRAS1, apoptotic cell death, caspase-dependent programmed cell death, NS6, malignant melanoma NOS (morphologic abnormality), Malignant Melanomas, apoptotic programmed cell death, type I programmed cell death, PRKMK7, Malignant, activation of apoptosis, MM - Malignant melanoma, Melanomas, signaling (initiator) caspase activity, Melanoma, induction of apoptosis, Malignant Melanoma, CMNS, ALPS4, Malignant melanoma (morphologic abnormality), MEK, Mek, NOS, malignant melanoma (disorder), Melanosarcoma, JNKK2, morphology (morphologic abnormality), NCMS, apoptosis signaling, N-ras, apoptosis, MKK7, Naevocarcinoma, MK., SAPKK-4, Malignant melanoma, MEK 7, apoptosis activator activity, no ICD-O subtype, induction of apoptosis by p53, [M]Malignant melanoma NOS (morphologic abnormality), no ICD-O subtype (morphologic abnormality), apoptotic program, [M]Malignant melanoma NOS, commitment to apoptosis, programmed cell death by apoptosis, AV095280extracellular signal-regulated kinase activity, pp44mapk, JTP74057, 4-Diazepine, Tyro5, 1H-1, Mpk2, malignant melanoma NOS (morphologic abnormality), p42mapk, Lion, Tumor, PRKMK7, type I programmed cell death, Herpailurus, Adprt1, LeMPK3, Extrinsic Pathway Apoptoses, GSK 269962A, p44mpk, Felis concolor, kinase-related transforming protein, symptoms, Malignant melanoma (morphologic abnormality), AT 877, Dp38, mitogen-activated protein kinase activity, SAPK2, drug resistance, ADPRT, NCMS, treatment, N-ras, Adprp, pp42, ARTD1, ADPRT1, AI893648, EK5, MP kinase activity, Intrinsic Pathway Apoptosis, Cougar, no ICD-O subtype (morphologic abnormality), medicine, Concentrations, disease management, MBP kinase II activity, Florida Panther, necrosis, PUMA, Tumors, cellular suicide, screening, MAP kinase 2 activity, SAPKK4, ERK-2, ERK1, pADPRT-1, ERK2, Erk2, Malignant Melanomas, PMK-2, PMK-1, tumours, PMK-3, DFNA13, Melanoma, p41mapk, signaling (initiator) caspase activity, induction of apoptosis, Intrinsic Pathway, MAPK, Extrinsic Pathway Apoptosis, NOS, concluding remarks, morphology (morphologic abnormality), Puma concolor, growth pattern, non-developmental growth, CAPB, conclusion, signs, p38, Mountain, DFNB53, experimental procedures, C78273, Intrinsic Pathway Apoptoses, summary, induction of apoptosis by p53, p41, ADPRT 1, p40, fasudil hydrochloride, Extrinsic Pathway, HKE5, 5830444G22Rik, AV095280, GSK1120212, Apoptoses, 9030612K14Rik, MAPKK7, JTP-74057, experimental, GSK-269962A, Neoplasms, NS6, drug susceptibility/resistance, caspase-dependent programmed cell death, JFY1, apoptotic programmed cell death, Malignant, activation of apoptosis, NEOPL, Hek5, AA407128, conclusions, JTP 74057, Florida, Mountain Lion, ALPS4, Prkm1, JFY-1, malignant melanoma (disorder), Melanosarcoma, p42-MAPK, Type I, JNKK2, C80510, ERK, PRKM1, study, PRKM2, methods, experimental section, MKK7, Naevocarcinoma, PCBC, tumour, MEK 7, apoptosis activator activity, p42 mitogen-activated protein kinase activity, ATP:protein phosphotransferase (MAPKK-activated) activity, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS), drugs, [M]Malignant melanoma NOS (morphologic abnormality), Concentration, execution phase of apoptotic process, [M]Malignant melanoma NOS, accidental cell death, STK26, p38-2, parp-1, programmed cell death by apoptosis, myelin basic protein kinase activity, Neoplastic Growth, Apoptosis, GSK 1120212, GSK269962A, HA 1077, Pumas, DRT, cell suicide, findings, NRAS1, drug, apoptotic cell death, MAP-2 kinase activity, NOS., Cell, MK, MM - Malignant melanoma, p38delta, GSK-1120212, Panther, Melanomas, sPARP-1, Malignant Melanoma, Programmed Cell Death, STL3, HA-1077, CMNS, Resistance, MBP kinase I activity, MEK, Mek, hexahydro-1-(5-isoquinolinylsulfonyl)-, Puma concolor coryi, fasudil mesylate, Death, AT877, apoptosis signaling, Cougars, apoptosis, PARP, mitogen activated kinase activity, P42MAPK, SAPKK-4, Malignant melanoma, Lions, MAPK2, AT-877, Drug, AU018647, no ICD-O subtype, ERT1, FBCG2, apoptotic program, EPHT3, PARP-1, Mountain Lions, commitment to apoptosis, 1-(5-isoquinolinesulfonyl)homopiperazine, PPOL, Attentions, NEOPLASMS BENIGN, Neoplasia, MAP kinase 1 activity2105http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320014056dbgap_ncbi~0patentfamilies~0rfam~0merops~0complex-portal~0uniprot~0wormbaseparasite~0embl-covid19~0reactome~0emdb~0wgs_masters~0ebiweb_resources~0opentargets_genetics~0biomodels_all~0ipd-mhc~0ebiweb_teams~0taxonomy~0genome_assembly~0sc-experiments~0ebiweb_people~0enzymeportal_enzymes~0ipd-nhkir~0cellosaurus~0pdbe~0chebi~0patentproteins~0interpro7~0uniref~0chembl~0pdbekb~0gpcrdb~0hgnc~0sc-genes~0intact~0rhea~0ebiweb_training~0alphafold~0imgt-hla~0patentnucleotides~0ensemblroot~0eva_studies~0non-coding~0europepmc~0pubmed~1identifiers_registry~0pdbechem~0hpa-covid19~0eva-variants-covid19~0biosamples~0gwas_catalog~0biotools~0tls_masters~0mesh~0coding~0sra~0opentargets~0efo~0embl-pathogen~0project~0pride~1human_diseases~0geo_datasets~0embl~0treefam~0uniparc~0ols~0dgva~0intenz~0go~0tsa_masters~0biosamples-covid19~0ebiweb_corporate~0omim~0lrg~0earlycause-molecular-sequences~0ipd-kir~0empiar~0rnacentral~0orcid_data_claims~0gpmdb~2lineage-covid19~0metagenomics~0pfam~0pride archive~1varsite~00Resource Reanalysis0.00.00.0064774830351634790.01.0falseCooperative induction of apoptosis in nras mutant melanoma by inhibition of mek and rockData from ProteomeXchange, PXD ID: PXD000528. Experiment: GM_NKI_NRAS_Phospho_Mix2, file: OR9_20130426_GM_NKI_NRAS_Phospho_Mix2_repl1_ReRunFr10.mzml. Published as part of Pigment Cell Melanoma Res. 2015 Feb 28 . From the Abstract: {{i}} No effective targeted therapy is currently available for NRAS mutant melanoma. Experimental MEK inhibition is rather toxic and has only limited efficacy in clinical trials. At least in part, this is caused by the emergence of drug resistance, which is commonly seen for single agent treatment and shortens clinical responses. Therefore, there is a dire need to identify effective companion drug targets for NRAS mutant melanoma. Here, we show that at concentrations where single drugs had little effect, ROCK inhibitors GSK269962A or Fasudil, in combination with either MEK inhibitor GSK1120212 (Trametinib) or ERK inhibitor SCH772984 cooperatively caused proliferation inhibition and cell death in vitro ... {{/i}}2015-03-14GPM3232001405625728708PXD000528PXD000528