PubMed:24185007 JSONTXT

{"project":"PubmedHPO","denotations":[{"id":"T1","span":{"begin":82,"end":101},"obj":"HP_0002861"},{"id":"T2","span":{"begin":92,"end":101},"obj":"HP_0002861"},{"id":"T3","span":{"begin":236,"end":242},"obj":"HP_0002664"},{"id":"T4","span":{"begin":328,"end":336},"obj":"HP_0002861"},{"id":"T5","span":{"begin":660,"end":668},"obj":"HP_0002861"},{"id":"T6","span":{"begin":1035,"end":1043},"obj":"HP_0002861"},{"id":"T7","span":{"begin":1159,"end":1166},"obj":"HP_0002664"}],"text":"A melanocyte lineage program confers resistance to MAP kinase pathway inhibition.\nMalignant melanomas harbouring point mutations (Val600Glu) in the serine/threonine-protein kinase BRAF (BRAF(V600E)) depend on RAF-MEK-ERK signalling for tumour cell growth. RAF and MEK inhibitors show remarkable clinical efficacy in BRAF(V600E) melanoma; however, resistance to these agents remains a formidable challenge. Global characterization of resistance mechanisms may inform the development of more effective therapeutic combinations. Here we carried out systematic gain-of-function resistance studies by expressing more than 15,500 genes individually in a BRAF(V600E) melanoma cell line treated with RAF, MEK, ERK or combined RAF-MEK inhibitors. These studies revealed a cyclic-AMP-dependent melanocytic signalling network not previously associated with drug resistance, including G-protein-coupled receptors, adenyl cyclase, protein kinase A and cAMP response element binding protein (CREB). Preliminary analysis of biopsies from BRAF(V600E) melanoma patients revealed that phosphorylated (active) CREB was suppressed by RAF-MEK inhibition but restored in relapsing tumours. Expression of transcription factors activated downstream of MAP kinase and cAMP pathways also conferred resistance, including c-FOS, NR4A1, NR4A2 and MITF. Combined treatment with MAPK-pathway and histone-deacetylase inhibitors suppressed MITF expression and cAMP-mediated resistance. Collectively, these data suggest that oncogenic dysregulation of a melanocyte lineage dependency can cause resistance to RAF-MEK-ERK inhibition, which may be overcome by combining signalling- and chromatin-directed therapeutics."}

{"project":"Allie","denotations":[{"id":"SS1_24185007_5_0","span":{"begin":939,"end":976},"obj":"expanded"},{"id":"SS2_24185007_5_0","span":{"begin":978,"end":982},"obj":"abbr"}],"relations":[{"id":"AE1_24185007_5_0","pred":"abbreviatedTo","subj":"SS1_24185007_5_0","obj":"SS2_24185007_5_0"}],"text":"A melanocyte lineage program confers resistance to MAP kinase pathway inhibition.\nMalignant melanomas harbouring point mutations (Val600Glu) in the serine/threonine-protein kinase BRAF (BRAF(V600E)) depend on RAF-MEK-ERK signalling for tumour cell growth. RAF and MEK inhibitors show remarkable clinical efficacy in BRAF(V600E) melanoma; however, resistance to these agents remains a formidable challenge. Global characterization of resistance mechanisms may inform the development of more effective therapeutic combinations. Here we carried out systematic gain-of-function resistance studies by expressing more than 15,500 genes individually in a BRAF(V600E) melanoma cell line treated with RAF, MEK, ERK or combined RAF-MEK inhibitors. These studies revealed a cyclic-AMP-dependent melanocytic signalling network not previously associated with drug resistance, including G-protein-coupled receptors, adenyl cyclase, protein kinase A and cAMP response element binding protein (CREB). Preliminary analysis of biopsies from BRAF(V600E) melanoma patients revealed that phosphorylated (active) CREB was suppressed by RAF-MEK inhibition but restored in relapsing tumours. Expression of transcription factors activated downstream of MAP kinase and cAMP pathways also conferred resistance, including c-FOS, NR4A1, NR4A2 and MITF. Combined treatment with MAPK-pathway and histone-deacetylase inhibitors suppressed MITF expression and cAMP-mediated resistance. Collectively, these data suggest that oncogenic dysregulation of a melanocyte lineage dependency can cause resistance to RAF-MEK-ERK inhibition, which may be overcome by combining signalling- and chromatin-directed therapeutics."}

{"project":"DisGeNET5_gene_disease","denotations":[{"id":"24185007-1#66#97#gene207","span":{"begin":148,"end":179},"obj":"gene207"},{"id":"24185007-1#66#97#gene65061","span":{"begin":148,"end":179},"obj":"gene65061"},{"id":"24185007-1#66#97#gene5127","span":{"begin":148,"end":179},"obj":"gene5127"},{"id":"24185007-1#66#97#gene22858","span":{"begin":148,"end":179},"obj":"gene22858"},{"id":"24185007-1#66#97#gene9020","span":{"begin":148,"end":179},"obj":"gene9020"},{"id":"24185007-1#66#97#gene55872","span":{"begin":148,"end":179},"obj":"gene55872"},{"id":"24185007-1#66#97#gene5568","span":{"begin":148,"end":179},"obj":"gene5568"},{"id":"24185007-1#66#97#gene9874","span":{"begin":148,"end":179},"obj":"gene9874"},{"id":"24185007-1#0#19#diseaseC0025202","span":{"begin":82,"end":101},"obj":"diseaseC0025202"},{"id":"24185007-2#0#3#gene5894","span":{"begin":256,"end":259},"obj":"gene5894"},{"id":"24185007-2#0#3#gene22882","span":{"begin":256,"end":259},"obj":"gene22882"},{"id":"24185007-2#8#11#gene5609","span":{"begin":264,"end":267},"obj":"gene5609"},{"id":"24185007-2#72#80#diseaseC0025202","span":{"begin":328,"end":336},"obj":"diseaseC0025202"},{"id":"24185007-6#38#49#gene673","span":{"begin":1023,"end":1034},"obj":"gene673"},{"id":"24185007-6#50#58#diseaseC0025202","span":{"begin":1035,"end":1043},"obj":"diseaseC0025202"}],"relations":[{"id":"66#97#gene2070#19#diseaseC0025202","pred":"associated_with","subj":"24185007-1#66#97#gene207","obj":"24185007-1#0#19#diseaseC0025202"},{"id":"66#97#gene650610#19#diseaseC0025202","pred":"associated_with","subj":"24185007-1#66#97#gene65061","obj":"24185007-1#0#19#diseaseC0025202"},{"id":"66#97#gene51270#19#diseaseC0025202","pred":"associated_with","subj":"24185007-1#66#97#gene5127","obj":"24185007-1#0#19#diseaseC0025202"},{"id":"66#97#gene228580#19#diseaseC0025202","pred":"associated_with","subj":"24185007-1#66#97#gene22858","obj":"24185007-1#0#19#diseaseC0025202"},{"id":"66#97#gene90200#19#diseaseC0025202","pred":"associated_with","subj":"24185007-1#66#97#gene9020","obj":"24185007-1#0#19#diseaseC0025202"},{"id":"66#97#gene558720#19#diseaseC0025202","pred":"associated_with","subj":"24185007-1#66#97#gene55872","obj":"24185007-1#0#19#diseaseC0025202"},{"id":"66#97#gene55680#19#diseaseC0025202","pred":"associated_with","subj":"24185007-1#66#97#gene5568","obj":"24185007-1#0#19#diseaseC0025202"},{"id":"66#97#gene98740#19#diseaseC0025202","pred":"associated_with","subj":"24185007-1#66#97#gene9874","obj":"24185007-1#0#19#diseaseC0025202"},{"id":"0#3#gene589472#80#diseaseC0025202","pred":"associated_with","subj":"24185007-2#0#3#gene5894","obj":"24185007-2#72#80#diseaseC0025202"},{"id":"0#3#gene2288272#80#diseaseC0025202","pred":"associated_with","subj":"24185007-2#0#3#gene22882","obj":"24185007-2#72#80#diseaseC0025202"},{"id":"8#11#gene560972#80#diseaseC0025202","pred":"associated_with","subj":"24185007-2#8#11#gene5609","obj":"24185007-2#72#80#diseaseC0025202"},{"id":"38#49#gene67350#58#diseaseC0025202","pred":"associated_with","subj":"24185007-6#38#49#gene673","obj":"24185007-6#50#58#diseaseC0025202"}],"text":"A melanocyte lineage program confers resistance to MAP kinase pathway inhibition.\nMalignant melanomas harbouring point mutations (Val600Glu) in the serine/threonine-protein kinase BRAF (BRAF(V600E)) depend on RAF-MEK-ERK signalling for tumour cell growth. RAF and MEK inhibitors show remarkable clinical efficacy in BRAF(V600E) melanoma; however, resistance to these agents remains a formidable challenge. Global characterization of resistance mechanisms may inform the development of more effective therapeutic combinations. Here we carried out systematic gain-of-function resistance studies by expressing more than 15,500 genes individually in a BRAF(V600E) melanoma cell line treated with RAF, MEK, ERK or combined RAF-MEK inhibitors. These studies revealed a cyclic-AMP-dependent melanocytic signalling network not previously associated with drug resistance, including G-protein-coupled receptors, adenyl cyclase, protein kinase A and cAMP response element binding protein (CREB). Preliminary analysis of biopsies from BRAF(V600E) melanoma patients revealed that phosphorylated (active) CREB was suppressed by RAF-MEK inhibition but restored in relapsing tumours. Expression of transcription factors activated downstream of MAP kinase and cAMP pathways also conferred resistance, including c-FOS, NR4A1, NR4A2 and MITF. Combined treatment with MAPK-pathway and histone-deacetylase inhibitors suppressed MITF expression and cAMP-mediated resistance. Collectively, these data suggest that oncogenic dysregulation of a melanocyte lineage dependency can cause resistance to RAF-MEK-ERK inhibition, which may be overcome by combining signalling- and chromatin-directed therapeutics."}

{"project":"DisGeNET5_variant_disease","denotations":[{"id":"24185007-6#43#48#geners113488022","span":{"begin":1028,"end":1033},"obj":"geners113488022"},{"id":"24185007-6#50#58#diseaseC0025202","span":{"begin":1035,"end":1043},"obj":"diseaseC0025202"}],"relations":[{"id":"43#48#geners11348802250#58#diseaseC0025202","pred":"associated_with","subj":"24185007-6#43#48#geners113488022","obj":"24185007-6#50#58#diseaseC0025202"}],"text":"A melanocyte lineage program confers resistance to MAP kinase pathway inhibition.\nMalignant melanomas harbouring point mutations (Val600Glu) in the serine/threonine-protein kinase BRAF (BRAF(V600E)) depend on RAF-MEK-ERK signalling for tumour cell growth. RAF and MEK inhibitors show remarkable clinical efficacy in BRAF(V600E) melanoma; however, resistance to these agents remains a formidable challenge. Global characterization of resistance mechanisms may inform the development of more effective therapeutic combinations. Here we carried out systematic gain-of-function resistance studies by expressing more than 15,500 genes individually in a BRAF(V600E) melanoma cell line treated with RAF, MEK, ERK or combined RAF-MEK inhibitors. These studies revealed a cyclic-AMP-dependent melanocytic signalling network not previously associated with drug resistance, including G-protein-coupled receptors, adenyl cyclase, protein kinase A and cAMP response element binding protein (CREB). Preliminary analysis of biopsies from BRAF(V600E) melanoma patients revealed that phosphorylated (active) CREB was suppressed by RAF-MEK inhibition but restored in relapsing tumours. Expression of transcription factors activated downstream of MAP kinase and cAMP pathways also conferred resistance, including c-FOS, NR4A1, NR4A2 and MITF. Combined treatment with MAPK-pathway and histone-deacetylase inhibitors suppressed MITF expression and cAMP-mediated resistance. Collectively, these data suggest that oncogenic dysregulation of a melanocyte lineage dependency can cause resistance to RAF-MEK-ERK inhibition, which may be overcome by combining signalling- and chromatin-directed therapeutics."}