Resistance mutation info of drug

Drug General Information
Drug ID D05ROI
Drug Name Dabrafenib Drug Info
Drug Type Small molecular drug
Structure D05ROI
Drug Resistance Mutations
Target Name Dual specificity mitogen-activated protein kinase kinase 1 (MAP2K1) Target Info
Gene Name MAP2K1
Uniprot ID MP2K1_HUMAN
Species Homo sapiens
Reference Sequence MPKKKPTPIQLNPAPDGSAVNGTSSAETNLEALQKKLEELELDEQQRKRLEAFLTQKQKV
GELKDDDFEKISELGAGNGGVVFKVSHKPSGLVMARKLIHLEIKPAIRNQIIRELQVLHE
CNSPYIVGFYGAFYSDGEISICMEHMDGGSLDQVLKKAGRIPEQILGKVSIAVIKGLTYL
REKHKIMHRDVKPSNILVNSRGEIKLCDFGVSGQLIDSMANSFVGTRSYMSPERLQGTHY
SVQSDIWSMGLSLVEMAVGRYPIPPPDAKELELMFGCQVEGDAAETPPRPRTPGRPLSSY
GMDSRPPMAIFELLDYIVNEPPPKLPSGVFSLEFQDFVNKCLIKNPAERADLKQLMVHAF
IKRSDAEEVDFAGWLCSTIGLNQPSTPTHAAGV [Homo sapiens]
Targeted Disease Melanoma
Drug Resistance Mutations
Mutation info Missense: P124S [555981]
Mutation Prevalence 1 out of 76 patients
Mutation info Missense: G128D [556039]
Mutation Prevalence 1 out of 10 patients
Mutation info Missense: K57E [555991]
Mutation Prevalence 1 out of 30 patients
Target Name Dual specificity mitogen-activated protein kinase kinase 2 (MAP2K2) Target Info
Gene Name MAP2K2
Uniprot ID MP2K2_HUMAN
Species Homo sapiens
Reference Sequence MLARRKPVLPALTINPTIAEGPSPTSEGASEANLVDLQKKLEELELDEQQKKRLEAFLTQ
KAKVGELKDDDFERISELGAGNGGVVTKVQHRPSGLIMARKLIHLEIKPAIRNQIIRELQ
VLHECNSPYIVGFYGAFYSDGEISICMEHMDGGSLDQVLKEAKRIPEEILGKVSIAVLRG
LAYLREKHQIMHRDVKPSNILVNSRGEIKLCDFGVSGQLIDSMANSFVGTRSYMAPERLQ
GTHYSVQSDIWSMGLSLVELAVGRYPIPPPDAKELEAIFGRPVVDGEEGEPHSISPRPRP
PGRPVSGHGMDSRPAMAIFELLDYIVNEPPPKLPNGVFTPDFQEFVNKCLIKNPAERADL
KMLTNHTFIKRSEVEEVDFAGWLCKTLRLNQPGTPTRTAV [Homo sapiens]
Targeted Disease Melanoma
Drug Resistance Mutations
Mutation info Missense: E207K [556039]
Mutation Prevalence 1 out of 10 patients
Mutation info Missense: V35M [555981]
Mutation info Missense: N126D [555981]
Mutation Prevalence 1 out of 76 patients
Mutation info Missense: L46F [555981]
Mutation Prevalence 3 out of 76 patients
Mutation info Missense: Q60P [555982], [556049]
Mutation Prevalence 3 out of 5 patients
Mutation info Missense: C125S [555981], [556039]
Mutation Prevalence 2 out of 10 patients
Target Name GTPase Nras (NRAS) Target Info
Gene Name NRAS
Uniprot ID RASN_HUMAN
Species Homo sapiens
Reference Sequence MTEYKLVVVGAGGVGKSALTIQLIQNHFVDEYDPTIEDSYRKQVVIDGETCLLDILDTAG
QEEYSAMRDQYMRTGEGFLCVFAINNSKSFADINLYREQIKRVKDSDDVPMVLVGNKCDL
PTRTVDTKQAHELAKSYGIPFIETSAKTRQGVEDAFYTLVREIRQYRMKKLNSSDDGTQG
CMGLPCVVM [Homo sapiens]
Targeted Disease Melanoma
Drug Resistance Mutations
Mutation info Missense: Q61K [555981]
Mutation Prevalence 4 out of 76 patients
Mutation info Missense: G12D [556039]
Mutation Prevalence 1 out of 10 patients
Target Name Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform (PIK3CA) Target Info
Gene Name PIK3CA
Uniprot ID PK3CA_HUMAN
Species Homo sapiens
Reference Sequence MPPRPSSGELWGIHLMPPRILVECLLPNGMIVTLECLREATLITIKHELFKEARKYPLHQ
LLQDESSYIFVSVTQEAEREEFFDETRRLCDLRLFQPFLKVIEPVGNREEKILNREIGFA
IGMPVCEFDMVKDPEVQDFRRNILNVCKEAVDLRDLNSPHSRAMYVYPPNVESSPELPKH
IYNKLDKGQIIVVIWVIVSPNNDKQKYTLKINHDCVPEQVIAEAIRKKTRSMLLSSEQLK
LCVLEYQGKYILKVCGCDEYFLEKYPLSQYKYIRSCIMLGRMPNLMLMAKESLYSQLPMD
CFTMPSYSRRISTATPYMNGETSTKSLWVINSALRIKILCATYVNVNIRDIDKIYVRTGI
YHGGEPLCDNVNTQRVPCSNPRWNEWLNYDIYIPDLPRAARLCLSICSVKGRKGAKEEHC
PLAWGNINLFDYTDTLVSGKMALNLWPVPHGLEDLLNPIGVTGSNPNKETPCLELEFDWF
SSVVKFPDMSVIEEHANWSVSREAGFSYSHAGLSNRLARDNELRENDKEQLKAISTRDPL
SEITEQEKDFLWSHRHYCVTIPEILPKLLLSVKWNSRDEVAQMYCLVKDWPPIKPEQAME
LLDCNYPDPMVRGFAVRCLEKYLTDDKLSQYLIQLVQVLKYEQYLDNLLVRFLLKKALTN
QRIGHFFFWHLKSEMHNKTVSQRFGLLLESYCRACGMYLKHLNRQVEAMEKLINLTDILK
QEKKDETQKVQMKFLVEQMRRPDFMDALQGFLSPLNPAHQLGNLRLEECRIMSSAKRPLW
LNWENPDIMSELLFQNNEIIFKNGDDLRQDMLTLQIIRIMENIWQNQGLDLRMLPYGCLS
IGDCVGLIEVVRNSHTIMQIQCKGGLKGALQFNSHTLHQWLKDKNKGEIYDAAIDLFTRS
CAGYCVATFILGIGDRHNSNIMVKDDGQLFHIDFGHFLDHKKKKFGYKRERVPFVLTQDF
LIVISKGAQECTKTREFERFQEMCYKAYLAIRQHANLFINLFSMMLGSGMPELQSFDDIA
YIRKTLALDKTEQEALEYFMKQMNDAHHGGWTTKMDWIFHTIKQHALN [Homo sapie
ns]
Targeted Disease Melanoma
Drug Resistance Mutations
Mutation info Missense: E545* [555983]
Target Name RAC-alpha serine/threonine-protein kinase (AKT1) Target Info
Gene Name AKT1
Uniprot ID AKT1_HUMAN
Species Homo sapiens
Reference Sequence MSDVAIVKEGWLHKRGEYIKTWRPRYFLLKNDGTFIGYKERPQDVDQREAPLNNFSVAQC
QLMKTERPRPNTFIIRCLQWTTVIERTFHVETPEEREEWTTAIQTVADGLKKQEEEEMDF
RSGSPSDNSGAEEMEVSLAKPKHRVTMNEFEYLKLLGKGTFGKVILVKEKATGRYYAMKI
LKKEVIVAKDEVAHTLTENRVLQNSRHPFLTALKYSFQTHDRLCFVMEYANGGELFFHLS
RERVFSEDRARFYGAEIVSALDYLHSEKNVVYRDLKLENLMLDKDGHIKITDFGLCKEGI
KDGATMKTFCGTPEYLAPEVLEDNDYGRAVDWWGLGVVMYEMMCGRLPFYNQDHEKLFEL
ILMEEIRFPRTLGPEAKSLLSGLLKKDPKQRLGGGSEDAKEIMQHRFFAGIVWQHVYEKK
LSPPFKPQVTSETDTRYFDEEFTAQMITITPPDQDDSMECVDSERRPHFPQFSYSASGTA
[Homo sapiens]
Targeted Disease Melanoma
Drug Resistance Mutations
Mutation info Missense: E17K [555980]
Mutation info Missense: Q79K [555980]
References
Ref 556264Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
Ref 555980A novel AKT1 mutant amplifies an adaptive melanoma response to BRAF inhibition. Cancer Discov. 2014 Jan;4(1):69-79. doi: 10.1158/2159-8290.CD-13-0279. Epub 2013 Nov 21.
Ref 555981The genetic landscape of clinical resistance to RAF inhibition in metastatic melanoma. Cancer Discov. 2014 Jan;4(1):94-109. doi: 10.1158/2159-8290.CD-13-0617. Epub 2013 Nov 21.
Ref 555982MAP kinase pathway alterations in BRAF-mutant melanoma patients with acquired resistance to combined RAF/MEK inhibition. Cancer Discov. 2014 Jan;4(1):61-8. doi: 10.1158/2159-8290.CD-13-0631. Epub 2013 Nov 21.
Ref 555983Acquired resistance and clonal evolution in melanoma during BRAF inhibitor therapy. Cancer Discov. 2014 Jan;4(1):80-93. doi: 10.1158/2159-8290.CD-13-0642. Epub 2013 Nov 21.
Ref 555991BRAF inhibitor resistance mechanisms in metastatic melanoma: spectrum and clinical impact. Clin Cancer Res. 2014 Apr 1;20(7):1965-77. doi: 10.1158/1078-0432.CCR-13-3122. Epub 2014 Jan 24.
Ref 556039Increased MAPK reactivation in early resistance to dabrafenib/trametinib combination therapy of BRAF-mutant metastatic melanoma. Nat Commun. 2014 Dec 2;5:5694. doi: 10.1038/ncomms6694.
Ref 556049Co-clinical assessment identifies patterns of BRAF inhibitor resistance in melanoma. J Clin Invest. 2015 Apr;125(4):1459-70. doi: 10.1172/JCI78954. Epub 2015 Feb 23.

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