Drug General Information
Drug ID	D0Y9EW
Drug Name	Vemurafenib
Synonyms	PLX4032; RG7204; RO5185426; Zelboraf (TN); Vemurafenib (BRAF inhibitor)
Drug Type	Small molecular drug
Company	Daiichi Sankyo group; Genentech
Structure
Drug Resistance Mutations
Target Name	Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase (PTEN)				Target Info
Gene Name	PTEN
Uniprot ID	PTEN_HUMAN
Species	Homo sapiens
Reference Sequence	MTAIIKEIVSRNKRRYQEDGFDLDLTYIYPNIIAMGFPAERLEGVYRNNIDDVVRFLDSK HKNHYKIYNLCAERHYDTAKFNCRVAQYPFEDHNPPQLELIKPFCEDLDQWLSEDDNHVA AIHCKAGKGRTGVMICAYLLHRGKFLKAQEALDFYGEVRTRDKKGVTIPSQRRYVYYYSY LLKNHLDYRPVALLFHKMMFETIPMFSGGTCNPQFVVCQLKVKIYSSNSGPTRREDKFMY FEFPQPLPVCGDIKVEFFHKQNKMLKKDKMFHFWVNTFFIPGPEETSEKVENGSLCDQEI DSICSIERADNDKEYLVLTLTKNDLDKANKDKANRYFSPNFKVKLYFTKTVEEPSNPEAS SSTSVTPDVSDNEPDHYRYSDTTDSDPENEPFDEDQHTQITKV [Homo sapiens]
Targeted Disease	Skin cancer
Drug Resistance Mutations	Mutation info Missense: R159S [1] Mutation Frequency 1 out of 26 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	Skin cancer
Drug Resistance Mutations	Mutation info Missense: Q61K [2], [3], [4] Mutation Frequency 4 out of 76 patients
	Mutation info Missense: Q61R [2], [3] Mutation Frequency 3 out of 76 patients
	Mutation info Missense: Q61H [3] Mutation Frequency 1 out of 76 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	Skin cancer
Drug Resistance Mutations	Mutation info Missense: V35M [3] Mutation Frequency 1 out of 76 patients
	Mutation info Missense: Q60P [5] Mutation Frequency 3 out of 5 patients
	Mutation info Missense: C125S [3] Mutation Frequency 1 out of 76 patients
	Mutation info Missense: F57C [8] Mutation Frequency 1 out of 30 patients
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	Skin cancer
Drug Resistance Mutations	Mutation info Missense: P124L [3] Mutation Frequency 1 out of 76 patients
	Mutation info Missense: E203K [6]
	Mutation info Missense: K57E [6]
	Mutation info Missense: G128V [3] Mutation Frequency 1 out of 76 patients
	Mutation info Missense: V60E [3] Mutation Frequency 1 out of 76 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	Skin cancer
Drug Resistance Mutations	Mutation info Missense: E545* [7]
	Mutation info Missense: E545K [9] Mutation Frequency 2 out of 278 patients
Target Name	Serine/threonine-protein kinase (B-raf)				Target Info
Gene Name	BRAF
Uniprot ID	BRAF_HUMAN
Species	Homo sapiens
Reference Sequence	MAALSGGGGGGAEPGQALFNGDMEPEAGAGAGAAASSAADPAIPEEVWNIKQMIKLTQEH IEALLDKFGGEHNPPSIYLEAYEEYTSKLDALQQREQQLLESLGNGTDFSVSSSASMDTV TSSSSSSLSVLPSSLSVFQNPTDVARSNPKSPQKPIVRVFLPNKQRTVVPARCGVTVRDS LKKALMMRGLIPECCAVYRIQDGEKKPIGWDTDISWLTGEELHVEVLENVPLTTHNFVRK TFFTLAFCDFCRKLLFQGFRCQTCGYKFHQRCSTEVPLMCVNYDQLDLLFVSKFFEHHPI PQEEASLAETALTSGSSPSAPASDSIGPQILTSPSPSKSIPIPQPFRPADEDHRNQFGQR DRSSSAPNVHINTIEPVNIDDLIRDQGFRGDGGSTTGLSATPPASLPGSLTNVKALQKSP GPQRERKSSSSSEDRNRMKTLGRRDSSDDWEIPDGQITVGQRIGSGSFGTVYKGKWHGDV AVKMLNVTAPTPQQLQAFKNEVGVLRKTRHVNILLFMGYSTKPQLAIVTQWCEGSSLYHH LHIIETKFEMIKLIDIARQTAQGMDYLHAKSIIHRDLKSNNIFLHEDLTVKIGDFGLATV KSRWSGSHQFEQLSGSILWMAPEVIRMQDKNPYSFQSDVYAFGIVLYELMTGQLPYSNIN NRDQIIFMVGRGYLSPDLSKVRSNCPKAMKRLMAECLKKKRDERPLFPQILASIELLARS LPKIHRSASEPSLNRAGFQTEDFSLYACASPKTPIQAGGYGAFPVH [Homo sapiens ]
Targeted Disease	Skin cancer
Drug Resistance Mutations	Mutation info Missense: L505H [9] Mutation Frequency 1 out of 10 patients
References
REF 1	Co-clinical assessment identifies patterns of BRAF inhibitor resistance in melanoma. J Clin Invest. 2015 Apr;125(4):1459-70.
REF 2	Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature. 2010 Dec 16;468(7326):973-7.
REF 3	The genetic landscape of clinical resistance to RAF inhibition in metastatic melanoma. Cancer Discov. 2014 Jan;4(1):94-109.
REF 4	Melanoma patient derived xenografts acquire distinct Vemurafenib resistance mechanisms. Am J Cancer Res. 2015 Mar 15;5(4):1507-18.
REF 5	MAP kinase pathway alterations in BRAF-mutant melanoma patients with acquired resistance to combined RAF/MEK inhibition. Cancer Discov. 2014 Jan;4(1):61-8.
REF 6	Pharmacodynamic effects and mechanisms of resistance to vemurafenib in patients with metastatic melanoma. J Clin Oncol. 2013 May 10;31(14):1767-74.
REF 7	Acquired resistance and clonal evolution in melanoma during BRAF inhibitor therapy. Cancer Discov. 2014 Jan;4(1):80-93.
REF 8	BRAF inhibitor resistance mechanisms in metastatic melanoma: spectrum and clinical impact. Clin Cancer Res. 2014 Apr 1;20(7):1965-77.
REF 9	Detailed imaging and genetic analysis reveal a secondary BRAF(L505H) resistance mutation and extensive intrapatient heterogeneity in metastatic BRAF mutant melanoma patients treated with vemurafenib. Pigment Cell Melanoma Res. 2015 May;28(3):318-23.

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