{"database":"EGA","file_versions":[],"scores":null,"additional":{"omics_type":["Genomics"],"technology_type":["Illumina HiSeq 2500, ILLUMINA"],"study_type":["Other"],"full_dataset_link":["https://ega-archive.org/studies/EGAS00001002846"],"host":["EGA"],"description":["EGA study EGAS00001002846"],"dataset_title":["Whole Exome Sequencing of a Melanoma Patient with Acquired Resistance to MEK plus CDK4/6 Inhibition"],"repository":["EGA"],"category":["restricted"],"name_synonyms":["Kinase Kinases, l(2)k06503, MEKs, MAPKK7, DSORT, dsor1, MAP-ERK Kinase, Complete Exome, xcdk4, MAPK-ERK Kinase, D-MEK/Dsor, cdk4/6, MEK1/2, Pk?7, PRKMK7, Malignant, D-mek, melanoma (disease), melanoma, cdk, Dmek, Su(Raf)34B, Whole Transcriptome, Transcriptome Sequencing, Kinase, JNKK2, CG15793, MAP, Map, treatment, WES, Complete, MAPK ERK Kinase, Exome Sequencings, MAPKKs, MAPK-ERK Kinases, CG5072, Complete Exome Sequencing, MKK7, Whole Transcriptome Sequencing, Naevocarcinoma, inhibiteur, PSK-J3, MEK 7, D-sor, DSor1, DSOR1, Sequencing, Map Kinase, Map Kinase Kinase, cdk4, Whole Exome, inhibidor, Kinase Kinase, Clients, Whole, CMM3, dCdk4, Therapies, CDK4, SOR, dSor1, Sor, D-Mek, D-MEK, l(2)05428, inhibitors, Therapy, Complete Exome Sequencings, SAPKK4, Mitogen-Activated Protein Kinase Kinase, sor/MEK1, MAP-ERK, D-sor-1, malignant, Exome, DSor, inhibitor, Malignant Melanomas, sor, Client, DRODSOR1, MK, l(2)s4639, MEK/Dsor1, Exome Sequencing, Melanomas, disease management., Melanoma, MAPK ERK Kinases, MAPK, Malignant Melanoma, MAP Kinase Kinases, MEK, Mek, MAP Kinase, DMEK-1, DmCdk4, Mitogen Activated Protein Kinase Kinase, dSor, D-SOR, D-Sor, EK1-1, antagonists, DmelCG15793, Complete Transcriptome, Complete Transcriptome Sequencing, MAPKK, MAP ERK Kinase, Mitogen Activated Protein Kinase Kinases, Kinases, mek, SAPKK-4, patient, Cdk4/6, Crk3, DmelCG5072, Treatments, dMEK, 8-6, CDK4/6, Patient, MAPK-ERK, antagonists and inhibitors, Therapeutic, Whole Exome Sequencing, l(2)0671, Dsor, Pk53C, malignant melanoma, Treatment, Transcriptome Sequencings, MAPK Kinase, l(2)sh0671, MAPK Kinases"],"description_synonyms":["Kinase Kinases, l(2)k06503, DmErk, extracellular signal-regulated kinase activity, pp44mapk, DSORT, dP60, PhrB photolyase activity, PROTEIN-SERINE KINASE, Vps34, Laboratory, Metastasis, 70 kDa ribosomal protein S6 kinase 1, ps6k, dp70s6k, MEK1/2, 10539, BcDNA:LD15217, fs(3)07084, neoplasm metastasis, Cyclin-dependent kinase 4 inhibitor A, AI314060, VPS34, 11621, Prp4 protein kinase activity, Mutations, PI-3 kinase, p110-alpha, LeMPK3, S6K-beta-1, cdk, ATP-protein transphosphorylase activity, p44mpk, ATP:protein phosphotransferase (non-specific) activity, p16-INK4, Dp38, protein-serine kinase 1, 3, Whole Transcriptome, Transcriptome Sequencing, Kinase, NUP96, Research Activity, SAPK2, epithelium, Laboratory Research, SEM, Sem, drug resistance, PS6K, p70[S6 kinase], Priorities, treatment, MAP-k, p70S6K, Dp60, Biopsies, MAPK-ERK Kinases, pp42, PI3K_59F, Dsor2, PI3-kinase activity, p70 S6K, DSor1, DSOR1, sem, PI3Kgamma, SUPPRESSOR OF AUXIN RESISTANCE 3, Map Kinase, MCAP, Map Kinase Kinase, geographical area, PI3K 68D, ATP - 1-phosphatidyl-1D-myo-inositol 3-phosphotransferase activity, ERK-A, p82 kinase activity, p70s6k, dVps34, Dp70S6k, dpERK, dpErk, rea, Exome, betaIIPKC, p50alpha, Research Priorities, DmMAPK, Malignant Melanomas, PMK-2, dp-ERK, PMK-1, not genetically inherited, CG2699, DmelCG5373, Expanded, PMK-3, Wee-kinase activity, p70s6K, s6k11, C530050K14, p70-S6K, 1270, type-1 PI3K, MAP Kinase Kinases, dipyrimidine photolyase (photosensitive), pMAPK, pMapK, DMEK-1, p70 ribosomal S6 kinase alpha, EK1-1, Research and Development, CG11621, Complete Transcriptome, DmERKA, rl/MAPK, CG10539, NRAS, expanded, Ex, l(3)07084, non-specific serine/threonine protein kinase activity, Cdk4/6, l(2)41Ac, DmelCG4141, F8A5_4, Activities, APDS, CT34260, dpERk, MAPK-ERK, Ribosomal protein S6 kinase I, serine-specific protein kinase activity, PI3KBETA, Whole Exome Sequencing, SAPK, HIPK2, cytidine 3', l(2)0671, School-Age Population, Wee 1-like kinase activity, INK4A, INK4B, MAPK Kinases, CDKN2, big, MEKs, glycogen synthase A kinase activity, p70-alpha, region or site annotation, INK4, MAPK-ERK Kinase, glycogen synthase kinase 3 activity, 12559, phosphorylase b kinase kinase activity, EK2-1, melanoma (disease), large, PIK3, DmelCG4114, Serine|threonine-protein kinase 14A, dVps34/PI3K59F, Pi3Kp60, PI3K-dp110, ALPS4, dPI3K, anon-92Ed, ribosomal protein S6 kinase II activity, MAP, Map, Erk, ERK, PRKM1, class I, School-Age Populations, PRKM2, protein-serine kinase activity, positional, Complete, Exome Sequencings, Naevocarcinoma, STK32, F23A5.3, MEK 7, Population, Pi3Kp110, p70|85s6k, Multiple tumor suppressor 1, Sequencing, erk, P110BETA, cdk4, Whole Exome, PI3K21B, protein-cysteine kinase activity, Kinase Kinase, Dp70[s6k], Whole, Hpr kinase activity, rll, CDK4, Development and Research, STK26, MCM, SOR, Sor, p38-2, l(2)05428, tumor metastasis, myelin basic protein kinase activity, Cpk, TP16, TP15, Complete Exome Sequencings, AA414921, MAP-ERK, NRAS1, Drug resistance, class II, Metastases, type III phosphoinositide 3-kinase activity, CG4114, stress-activated kinase activity, MAP-2 kinase activity, AA959758, sor, protein serine kinase activity, PK6, p70/85s6k, PI(3)K, MK, protein phosphokinase activity, cpk, PI3K-92E/Dp110, Metastase, Exome Sequencing, PIK3C1, PKA, MAPK ERK Kinases, PKC, CWS5, P14ARF, dp70[S6k], Malignant Melanoma, stress-activated protein kinase activity, chemical analysis, mapk2, mapk1, Resistance, Neoplasm, MEK, Mek, MAP Kinase, protein kinase p58 activity, p16INK4A, P16INK4A, serine/threonine protein kinase activity, RPE, CG12559, Mitogen Activated Protein Kinase Kinases, dpERK1, mek, ARABIDOPSIS THALIANA PROTEIN-SERINE KINASE 1, Crk3, DmelCG11621, dsk1, School Age Populations, primary structure of sequence macromolecule, ARABIDOPSIS THALIANA PROTEIN-SERINE KINASE 6, 5'-cyclic monophosphate-responsive protein kinase activity, atypical PKC activity, DmelCG10539, p. pigmentosa retinae, l(2)01270, caPI3K, CLOVE, dpMAPK, DmVps34, P70S6K1, IMD14, PI3K_68D, PI3K-92D, Pk53C, deoxyribonucleate pyrimidine dimer lyase (photosensitive), Dmp110, protein serine-threonine kinase activity, SAP kinase activity, 4732464A07Rik, glycogen synthase kinase activity, MTS1, MTS2, dsor1, MAP-ERK Kinase, insensitive, protein kinase A activity, CG5373, Activity, determination, ATVPS34, rps6kb1-A, Mpk2, D-MEK/Dsor, cdk4/6, p42mapk, PI3K, Dp110, Neoplasm Metastases, PRKMK7, pigmented epithelium, brl, cancer metastasis, SR2-1, School-Age, PHOSPHATIDYLINOSITOL 3-KINASE, sampling, melanoma, DmelCG2699, F8A5.4, kinase-related transforming protein, Su(Raf)34B, p110alpha, mitogen-activated protein kinase activity, ARF, p16-INK4a, p70(S6K)-alpha, phosphatidylinositol 3-kinase activity, mpk1, NCMS, N-ras, Erk/Map kinase, P70 RIBOSOMAL S6 KINASE, Pi3K92D, CG4141, Complete Exome Sequencing, Whole Transcriptome Sequencing, STK14A, catalyst activity, pigmented retina, DERK-A, MTS-1, Pi3k, E(sina)7, PI[[3]]K, Rl, DNA cyclobutane dipyrimidine photolyase activity, Raf kinase activity, MP kinase activity, serine kinase activity, DERK, p55alpha, p70 S6 kinase alpha, S6K, atypical protein kinase C activity, dCdk4, disease management, Therapies, MBP kinase II activity, mitogen-activated S6 kinase activity, P14, protein-aspartyl kinase activity, P16, dERK, Pi3K, PI3k, P15, Research Priority, dSor1, P19, MCMTC, P16-INK4A, droPIK57., Therapy, PRE, PI3K68D, MAP kinase 2 activity, SAPKK4, sor/MEK1, D-sor-1, Mapk, P110DELTA, PtdIns-3-kinase activity, MLM, deoxyribonucleic cyclobutane dipyrimidine photolyase activity, DSor, Erk1, ERK1, ERK2, mapk1a, DRODSOR1, p70 S6KA, s6K1, results, vacuolar protein sorting 34, AI256796, dPIK, 1-phosphatidylinositol 3-kinase activity, M phase-specific cdc2 kinase activity, Melanoma, retinal pigment, s6k, mapk1b, MapK, MAPK, School Age, serine protein kinase activity, Mitogen Activated Protein Kinase Kinase, retinal pigment layer, erk2, dSor, mapk, Populations, ERKa, phosphorylase B kinase kinase activity, MAP ERK Kinase, positional polypeptide feature, BcDNA:RE08694, resistant, protein glutamyl kinase activity, ROTEIN-SERINE KINASE 6, p85alpha, l(2R)EMS45-39, ATS6K1, DmelCG12559, initiation, common, p38, PI3K 68_D, Treatments, DpErk, DpERK, dMEK, ErkA, ERKA, CDK4/6, phr A photolyase activity, hydroxyalkyl-protein kinase activity, stk14a, WEE1Hu, p110D, DNA-photoreactivating enzyme, Patient, enlarged, epsilon PKC, S6K1, l(2)ey, Dsor, p120-PI3K, AV095280, Transcriptome Sequencings, MAPK Kinase, pERK, ribosomal S6 protein kinase activity, p70-S6K 1, MAPKK7, calcium/phospholipid-dependent protein kinase activity, GroupII, xcdk4, Complete Exome, p70[S6k], PI3K92E, NS6, drug susceptibility/resistance, Pi3K_59F, Pk?7, photoreactivating enzyme activity, type I phosphatidylinositol kinase activity, Malignant, D-mek, phosphatidylinositol 3-kinase, dps6k, p60, p70[S6K], resistance, Dmek, serine(threonine) protein kinase activity, ATPK6, stratum pigmentosa retinae, PHOSPATIDYLINOSITOL 3-KINASE, ATPK1, JNKK2, CG15793, Dp110/PI3K, T-antigen kinase activity, PI3K-68D/E, galactosyltransferase-associated kinase activity, tumor cell migration, WES, MAPK ERK Kinase, MOS3, deoxyribocyclobutadipyrimidine pyrimidine-lyase activity, p70[S6kinase], MAPKKs, PRECOCIOUS, Research, CG5072, MKK7, xp42, metastasis, PSK-J3, PI3'K, D-sor, p42 mitogen-activated protein kinase activity, CG18732, ATP:protein phosphotransferase (MAPKK-activated) activity, protein kinase (phosphorylating) activity, PI3K-68D, Dp70s6k, Raf-1, p70-s6k, Clients, great, CMM3, CMM2, DmERK-A, School Age Population, D-Mek, D-MEK, casein kinase (phosphorylating) activity, F23A5_3, dP110, DS6K, ert1, P16INK4, 6330412C24Rik, Mitogen-Activated Protein Kinase Kinase, dS6k, 7084, p120, malignant, prkm2, prkm1, CT39192, p110, Vps34p, Client, l(2)s4639, p70 S6K-alpha, MEK/Dsor1, p38delta, Melanomas, MODIFIER OF SNC1, 2.7.11.1, twitchin kinase activity, Priority, ATP:1-phosphatidyl-1D-myo-inositol 3-phosphotransferase activity, vps34, dS6K, AP50 kinase activity, deoxyribonucleic photolyase activity, Research Activities, 2610318I15Rik, CMNS, MBP kinase I activity, dp110, sequence, rare (European definition), PI3CG, DmCdk4, D-SOR, D-Sor, Xp42, PI-3-K, DmelCG15793, threonine-specific protein kinase activity, PI3K-59F, MAPKK, Complete Transcriptome Sequencing, PI3K-Dp110, photolyase activity, Kinases, mitogen activated kinase activity, Su(Raf)2B, p15INK4b, CDK4I, response to drug, 70kDa, class III, SAPKK-4, patient, EY2-2, DmelCG5072, p110gamma, Drug, 8-6, sample collection, D-ERK, Therapeutic, ds6k, P19ARF, p70/S6K, malignant melanoma, Treatment, assay, l(2)sh0671, MAP kinase 1 activity, A-kinase activity"],"additional_accession":[]},"is_claimable":false,"name":"Whole exome sequencing of longitudinal samples from a melanoma patient receiving MEK plus CDK4/6 inhibitor therapy.","description":"Combined MEK and CDK4/6 inhibition (MEKi+CDK4i) has shown promising clinical outcomes in NRAS mutant melanoma patients. Here, we interrogated longitudinal biopsies from a patient who initially responded to MEKi+CDK4i therapy but subsequently developed resistance. Whole exome sequencing and functional validation identified an acquired PIK3CAE545K mutation as conferring drug resistance. We demonstrate that PIK3CAE545K pre-existed in a rare subpopulation that was missed by both clinical and research testing, but was revealed upon multi-region sampling due to PIK3CAE545K being non-uniformly distributed. This resistant population rapidly expanded after the initiation of MEKi+CDK4i therapy and persisted in all successive samples even after immune checkpoint therapy and distant metastasis.  Functional studies identified activated S6K1 as both a key marker and specific therapeutic vulnerability downstream of PIK3CAE545K-induced resistance. These results demonstrate that comprehensive analysis of pre-treatment samples can reveal rare pre-existing resistant subpopulations and also posit S6K1 as a common downstream therapeutic nexus for the MAPK, CDK4/6, and PI3K pathways.","dates":{"updated":"2018-03-02 10:50:59"},"accession":"EGAS00001002846","cross_references":{"TAXONOMY":["9606"],"EGA":["EGAD00001003989","EGAC00001000839"]}}