Resistance mutation info of drug

Drug General Information
Drug ID D0N5OV
Drug Name Cetuximab Drug Info
Synonyms Erbitux; Cetuximab (genetical recombination); Erbitux (TN); Cetuximab (USAN/INN); Cetuximab (genetical recombination) (JAN)
Drug Type Antibody
Therapeutic Class Anticancer Agents
Company Bristol-Myers Squibb
Drug Resistance Mutations
Target Name Epidermal growth factor receptor (EGFR) Target Info
Gene Name EGFR
Uniprot ID EGFR_HUMAN
Species Homo sapiens
Reference Sequence MRPSGTAGAALLALLAALCPASRALEEKKVCQGTSNKLTQLGTFEDHFLSLQRMFNNCEV
VLGNLEITYVQRNYDLSFLKTIQEVAGYVLIALNTVERIPLENLQIIRGNMYYENSYALA
VLSNYDANKTGLKELPMRNLQEILHGAVRFSNNPALCNVESIQWRDIVSSDFLSNMSMDF
QNHLGSCQKCDPSCPNGSCWGAGEENCQKLTKIICAQQCSGRCRGKSPSDCCHNQCAAGC
TGPRESDCLVCRKFRDEATCKDTCPPLMLYNPTTYQMDVNPEGKYSFGATCVKKCPRNYV
VTDHGSCVRACGADSYEMEEDGVRKCKKCEGPCRKVCNGIGIGEFKDSLSINATNIKHFK
NCTSISGDLHILPVAFRGDSFTHTPPLDPQELDILKTVKEITGFLLIQAWPENRTDLHAF
ENLEIIRGRTKQHGQFSLAVVSLNITSLGLRSLKEISDGDVIISGNKNLCYANTINWKKL
FGTSGQKTKIISNRGENSCKATGQVCHALCSPEGCWGPEPRDCVSCRNVSRGRECVDKCN
LLEGEPREFVENSECIQCHPECLPQAMNITCTGRGPDNCIQCAHYIDGPHCVKTCPAGVM
GENNTLVWKYADAGHVCHLCHPNCTYGCTGPGLEGCPTNGPKIPSIATGMVGALLLLLVV
ALGIGLFMRRRHIVRKRTLRRLLQERELVEPLTPSGEAPNQALLRILKETEFKKIKVLGS
GAFGTVYKGLWIPEGEKVKIPVAIKELREATSPKANKEILDEAYVMASVDNPHVCRLLGI
CLTSTVQLITQLMPFGCLLDYVREHKDNIGSQYLLNWCVQIAKGMNYLEDRRLVHRDLAA
RNVLVKTPQHVKITDFGLAKLLGAEEKEYHAEGGKVPIKWMALESILHRIYTHQSDVWSY
GVTVWELMTFGSKPYDGIPASEISSILEKGERLPQPPICTIDVYMIMVKCWMIDADSRPK
FRELIIEFSKMARDPQRYLVIQGDERMHLPSPTDSNFYRALMDEEDMDDVVDADEYLIPQ
QGFFSSPSTSRTPLLSSLSATSNNSTVACIDRNGLQSCPIKEDSFLQRYSSDPTGALTED
SIDDTFLPVPEYINQSVPKRPAGSVQNPVYHNQPLNPAPSRDPHYQDPHSTAVGNPEYLN
TVQPTCVNSTFDSPAHWAQKGSHQISLDNPDYQQDFFPKEAKPNGIFKGSTAENAEYLRV
APQSSEFIGA [Homo sapiens]
Targeted Disease Colorectal cancer
Drug Resistance Mutations
Mutation info Missense: S492R [555841]
Mutation Prevalence 2 out of 10 patients
Mutation info Missense: K467T [555841], [556042], [556066], [556110]
Mutation info Missense: R451C [555841], [556042], [556066], [556110]
Mutation info Missense: G465R [555841], [556042], [556066], [556110]
Mutation info Missense: I491M [556042]
Mutation info Missense: S464L [556042]
Target Name GTPase Kras (KRAS)
Gene Name KRAS
Uniprot ID RASK_HUMAN
Species Homo sapiens
Reference Sequence MTEYKLVVVGAGGVGKSALTIQLIQNHFVDEYDPTIEDSYRKQVVIDGETCLLDILDTAG
QEEYSAMRDQYMRTGEGFLCVFAINNTKSFEDIHHYREQIKRVKDSEDVPMVLVGNKCDL
PSRTVDTKQAQDLARSYGIPFIETSAKTRQRVEDAFYTLVREIRQYRLKKISKEEKTPGC
VKIKKCIIM [Homo sapiens]
Targeted Disease Colorectal cancer
Drug Resistance Mutations
Mutation info Missense: G13D [556123]
Mutation Prevalence 19% of the patients in all Kras mutations
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 Colorectal cancer
Drug Resistance Mutations
Mutation info Missense: V600E [555762], [555786], [555915]
Mutation Prevalence 95% of the patients in all RAF mutation
References
Ref 5274662004 approvals: the demise of the blockbuster. Nat Rev Drug Discov. 2005 Feb;4(2):93-4.
Ref 541939(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 6882).
Ref 555762Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis. Lancet Oncol. 2010 Aug;11(8):753-62. doi: 10.1016/S1470-2045(10)70130-3. Epub 2010 Jul 8.
Ref 555786KRAS, BRAF, PIK3CA, and PTEN mutations: implications for targeted therapies in metastatic colorectal cancer. Lancet Oncol. 2011 Jun;12(6):594-603. doi: 10.1016/S1470-2045(10)70209-6. Epub 2010 Dec 14.
Ref 555841Identification of a mutation in the extracellular domain of the Epidermal Growth Factor Receptor conferring cetuximab resistance in colorectal cancer. Nat Med. 2012 Jan 22;18(2):221-3. doi: 10.1038/nm.2609.
Ref 555915Massively parallel tumor multigene sequencing to evaluate response to panitumumab in a randomized phase III study of metastatic colorectal cancer. Clin Cancer Res. 2013 Apr 1;19(7):1902-12. doi: 10.1158/1078-0432.CCR-12-1913. Epub 2013 Jan 16.
Ref 556042Emergence of Multiple EGFR Extracellular Mutations during Cetuximab Treatment in Colorectal Cancer. Clin Cancer Res. 2015 May 1;21(9):2157-66. doi: 10.1158/1078-0432.CCR-14-2821. Epub 2015 Jan 26.
Ref 556066Epidermal growth factor receptor mutation mediates cross-resistance to panitumumab and cetuximab in gastrointestinal cancer. Oncotarget. 2015 May 20;6(14):12035-47.
Ref 556110The First-in-class Anti-EGFR Antibody Mixture Sym004 Overcomes Cetuximab Resistance Mediated by EGFR Extracellular Domain Mutations in Colorectal Cancer. Clin Cancer Res. 2016 Jul 1;22(13):3260-7. doi: 10.1158/1078-0432.CCR-15-2400. Epub 2016 Feb 17.
Ref 556123Response to Cetuximab With or Without Irinotecan in Patients With Refractory Metastatic Colorectal Cancer Harboring the KRAS G13D Mutation: Australasian Gastro-Intestinal Trials Group ICECREAM Study. J Clin Oncol. 2016 Jul 1;34(19):2258-64. doi: 10.1200/JCO.2015.65.6843. Epub 2016 Apr 25.

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