Garnett, Mathew
Mathew's research team investigate how genetic alterations contribute to cancer and impact on patient responses to anti-cancer medicines.
This provides fundamental insights into cancer biology with direct links to the development of new cancer therapies.
Mathew's expertise is in molecular cell biology, high-throughput chemical and genetic screens, cancer genomics and anti-cancer therapeutics.
Mathew joined the Sanger Institute in 2009 as a Senior Staff Scientist and was appointed a member of Faculty in 2014. Here he developed high-throughput single-agent and combination drug sensitivity screens in cancer cells to identify molecular features of cells that are predictive of drug response to help inform the development of new anti-cancer therapies. This work is on-going but has already led to the identification of new putative molecular biomarkers with potential to improve cancer treatments and contributed to the initiation of clinical trials.
In addition, he is performing CRISPR-Cas9 genetic screens in cancer cells to identify new drug targets, which led to the discovery of Werner Syndrome helicase as a synthetic-lethal target in microsatellite unstable cancers. Mathew is also passionate about developing new cancer models such as 3D organoid cultures which better capture the heterogeneity and hallmarks of patient tumours.
Mathew's lab have developed three leading public therapeutics web portals. The Genomics of Drug Sensitivity in Cancer (GDSC) hosts drug sensitivity data and biomarker analyses to help inform the development of new cancer therapies. The Project Score database hosts CRISPR screening datasets to prioritise candidate oncology targets. The Cell Model Passports database is a hub for accessing cell model genetic and functional datasets, containing data for 1600 cell lines and most recently organoid cultures These databases and associated datasets are part of the Cancer Dependency Map, which aims to exhaustively identify vulnerabilities in human cancers to guide future precision cancer medicines
Mathew is a member of the scientific leadership team for the Open Targets, which aims to use genome-scale experiments and analysis to evaluate new therapeutic targets, as well as a member of the Cancer Research UK drug discovery small molecule expert review panel.
Prior to joining the Sanger Institute, Mathew performed his postdoctoral work in the laboratory of Professor Ashok Venkitaraman (Cambridge University, UK) with a fellowship from the Canadian Institute of Health Research. Here he developed small interfering RNA screens using high-content microscopy to understand how cells respond to anti-mitotic cancer drugs. Mathew identified the ubiquitin-conjugating enzyme UBE2S as a novel regulator of the Anaphase Promoting Complex (APC). UBE2S is necessary for ubiquitination of APC substrates, allowing progression through mitosis following mitotic checkpoint inactivation. This work identified a new component of the mitotic checkpoint machinery, provided fresh insights into the regulation of APC activity and contributed towards our understanding of the mechanisms that control the cellular response to mitotic checkpoint arrest.
Mathew completed his PhD in 2005 in the laboratory of Richard Marais at The Institute of Cancer Research (London, UK), where he was involved in the discovery and characterisation of BRAF as a human cancer gene. His PhD work elucidated how cancer-associated mutations perturb RAF activity and demonstrated that RAF-family kinases oligomerise in cells to activate the ERK-pathway, identifying a new paradigm in the regulation of RAF signalling. This was subsequently shown to have important implications for clinical deployment of therapies targeting RAF proteins in cancer.
Mathew graduated in 1999 with a BSc. in Biochemistry (Hons.) from the University of British Columbia, Canada.
Throughout Mathew's scientific career he has strived to understand how genetic changes in cancers can be exploited to develop new cancer therapies. Several of his publications are highly cited, he has generated widely used reference datasets for the community, and his research has directly contributed to the development and testing of new cancer therapies. Mathew fosters a multi-disciplinary and collaborative approach in his research team to enable the best possible research.
Publications
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Prioritization of cancer therapeutic targets using CRISPR-Cas9 screens.
Nature 2019;568;7753;511-516
PUBMED: 30971826; DOI: 10.1038/s41586-019-1103-9
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Functional linkage of gene fusions to cancer cell fitness assessed by pharmacological and CRISPR-Cas9 screening.
Nature communications 2019;10;1;2198
PUBMED: 31097696; PMC: 6522557; DOI: 10.1038/s41467-019-09940-1
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Cell Model Passports-a hub for clinical, genetic and functional datasets of preclinical cancer models.
Nucleic acids research 2019;47;D1;D923-D929
PUBMED: 30260411; PMC: 6324059; DOI: 10.1093/nar/gky872
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Organoid cultures recapitulate esophageal adenocarcinoma heterogeneity providing a model for clonality studies and precision therapeutics.
Nature communications 2018;9;1;2983
PUBMED: 30061675; PMC: 6065407; DOI: 10.1038/s41467-018-05190-9
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A Landscape of Pharmacogenomic Interactions in Cancer.
Cell 2016;166;3;740-754
PUBMED: 27397505; PMC: 4967469; DOI: 10.1016/j.cell.2016.06.017
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Prospective derivation of a living organoid biobank of colorectal cancer patients.
Cell 2015;161;4;933-45
PUBMED: 25957691; PMC: 6428276; DOI: 10.1016/j.cell.2015.03.053
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Genomics of Drug Sensitivity in Cancer (GDSC): a resource for therapeutic biomarker discovery in cancer cells.
Nucleic acids research 2013;41;Database issue;D955-61
PUBMED: 23180760; PMC: 3531057; DOI: 10.1093/nar/gks1111
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Systematic identification of genomic markers of drug sensitivity in cancer cells.
Nature 2012;483;7391;570-5
PUBMED: 22460902; PMC: 3349233; DOI: 10.1038/nature11005
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UBE2S elongates ubiquitin chains on APC/C substrates to promote mitotic exit.
Nature cell biology 2009;11;11;1363-9
PUBMED: 19820702; PMC: 2875106; DOI: 10.1038/ncb1983
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Wild-type and mutant B-RAF activate C-RAF through distinct mechanisms involving heterodimerization.
Molecular cell 2005;20;6;963-9
PUBMED: 16364920; DOI: 10.1016/j.molcel.2005.10.022
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Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF.
Cell 2004;116;6;855-67
PUBMED: 15035987; DOI: 10.1016/s0092-8674(04)00215-6
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Quantitative Proteome Landscape of the NCI-60 Cancer Cell Lines.
iScience 2019;21;664-680
PUBMED: 31733513; DOI: 10.1016/j.isci.2019.10.059
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Patient-derived xenografts and matched cell lines identify pharmacogenomic vulnerabilities in colorectal cancer.
Clinical cancer research : an official journal of the American Association for Cancer Research 2019
PUBMED: 31375513; DOI: 10.1158/1078-0432.CCR-18-3440
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Community assessment to advance computational prediction of cancer drug combinations in a pharmacogenomic screen.
Nature communications 2019;10;1;2674
PUBMED: 31209238; PMC: 6572829; DOI: 10.1038/s41467-019-09799-2
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Imipridone ONC212 activates orphan G protein-coupled receptor GPR132 and integrated stress response in acute myeloid leukemia.
Leukemia 2019
PUBMED: 31127149; DOI: 10.1038/s41375-019-0491-z
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Functional linkage of gene fusions to cancer cell fitness assessed by pharmacological and CRISPR-Cas9 screening.
Nature communications 2019;10;1;2198
PUBMED: 31097696; PMC: 6522557; DOI: 10.1038/s41467-019-09940-1
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Prioritization of cancer therapeutic targets using CRISPR-Cas9 screens.
Nature 2019;568;7753;511-516
PUBMED: 30971826; DOI: 10.1038/s41586-019-1103-9
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Characterizing Mutational Signatures in Human Cancer Cell Lines Reveals Episodic APOBEC Mutagenesis.
Cell 2019;176;6;1282-1294.e20
PUBMED: 30849372; PMC: 6424819; DOI: 10.1016/j.cell.2019.02.012
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JACKS: joint analysis of CRISPR/Cas9 knockout screens.
Genome research 2019;29;3;464-471
PUBMED: 30674557; PMC: 6396427; DOI: 10.1101/gr.238923.118
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Structural rearrangements generate cell-specific, gene-independent CRISPR-Cas9 loss of fitness effects.
Genome biology 2019;20;1;27
PUBMED: 30722791; PMC: 6362594; DOI: 10.1186/s13059-019-1637-z
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Cell Model Passports-a hub for clinical, genetic and functional datasets of preclinical cancer models.
Nucleic acids research 2019;47;D1;D923-D929
PUBMED: 30260411; PMC: 6324059; DOI: 10.1093/nar/gky872
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Drug Sensitivity Assays of Human Cancer Organoid Cultures.
Methods in molecular biology (Clifton, N.J.) 2019;1576;339-351
PUBMED: 27628132; PMC: 6527507; DOI: 10.1007/7651_2016_10
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NOTCH1 Represses MCL-1 Levels in GSI-resistant T-ALL, Making them Susceptible to ABT-263.
Clinical cancer research : an official journal of the American Association for Cancer Research 2019;25;1;312-324
PUBMED: 30224339; PMC: 6320296; DOI: 10.1158/1078-0432.CCR-18-0867
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CellMinerCDB for Integrative Cross-Database Genomics and Pharmacogenomics Analyses of Cancer Cell Lines.
iScience 2018;10;247-264
PUBMED: 30553813; PMC: 6302245; DOI: 10.1016/j.isci.2018.11.029
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The germline genetic component of drug sensitivity in cancer cell lines.
Nature communications 2018;9;1;3385
PUBMED: 30139972; PMC: 6107640; DOI: 10.1038/s41467-018-05811-3
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Unsupervised correction of gene-independent cell responses to CRISPR-Cas9 targeting.
BMC genomics 2018;19;1;604
PUBMED: 30103702; PMC: 6088408; DOI: 10.1186/s12864-018-4989-y
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Organoid cultures recapitulate esophageal adenocarcinoma heterogeneity providing a model for clonality studies and precision therapeutics.
Nature communications 2018;9;1;2983
PUBMED: 30061675; PMC: 6065407; DOI: 10.1038/s41467-018-05190-9
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Itraconazole targets cell cycle heterogeneity in colorectal cancer.
The Journal of experimental medicine 2018
PUBMED: 29853607; DOI: 10.1084/jem.20171385
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The Origins and Vulnerabilities of Two Transmissible Cancers in Tasmanian Devils.
Cancer cell 2018;33;4;607-619.e15
PUBMED: 29634948; PMC: 5896245; DOI: 10.1016/j.ccell.2018.03.013
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Transcription Factor Activities Enhance Markers of Drug Sensitivity in Cancer.
Cancer research 2018;78;3;769-780
PUBMED: 29229604; PMC: 6522379; DOI: 10.1158/0008-5472.CAN-17-1679
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Comprehensive Pharmacogenomic Profiling of Malignant Pleural Mesothelioma Identifies a Subgroup Sensitive to FGFR Inhibition.
Clinical cancer research : an official journal of the American Association for Cancer Research 2018;24;1;84-94
PUBMED: 29061644; DOI: 10.1158/1078-0432.CCR-17-1172
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Single agent and synergistic combinatorial efficacy of first-in-class small molecule imipridone ONC201 in hematological malignancies.
Cell cycle (Georgetown, Tex.) 2017;1-29
PUBMED: 29157092; DOI: 10.1080/15384101.2017.1403689
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High-throughput RNAi screen for essential genes and drug synergistic combinations in colorectal cancer.
Scientific data 2017;4;170139
PUBMED: 28972570; PMC: 5625556; DOI: 10.1038/sdata.2017.139
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Drug Resistance Mechanisms in Colorectal Cancer Dissected with Cell Type-Specific Dynamic Logic Models.
Cancer research 2017;77;12;3364-3375
PUBMED: 28381545; PMC: 6433282; DOI: 10.1158/0008-5472.CAN-17-0078
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A Road Map for Precision Cancer Medicine Using Personalized Models.
Cancer discovery 2017;7;5;456-458
PUBMED: 28461408; DOI: 10.1158/2159-8290.CD-17-0268
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Genome-wide chemical mutagenesis screens allow unbiased saturation of the cancer genome and identification of drug resistance mutations.
Genome research 2017;27;4;613-625
PUBMED: 28179366; PMC: 5378179; DOI: 10.1101/gr.213546.116
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Revisiting olfactory receptors as putative drivers of cancer.
Wellcome open research 2017;2;9
PUBMED: 28492065; PMC: 5421569; DOI: 10.12688/wellcomeopenres.10646.1
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Logic models to predict continuous outputs based on binary inputs with an application to personalized cancer therapy.
Scientific reports 2016;6;36812
PUBMED: 27876821; PMC: 5120272; DOI: 10.1038/srep36812
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A Biobank of Breast Cancer Explants with Preserved Intra-tumor Heterogeneity to Screen Anticancer Compounds.
Cell 2016;167;1;260-274.e22
PUBMED: 27641504; PMC: 5037319; DOI: 10.1016/j.cell.2016.08.041
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A Landscape of Pharmacogenomic Interactions in Cancer.
Cell 2016;166;3;740-754
PUBMED: 27397505; PMC: 4967469; DOI: 10.1016/j.cell.2016.06.017
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Isocitrate dehydrogenase mutations confer dasatinib hypersensitivity and SRC-dependence in intrahepatic cholangiocarcinoma.
Cancer discovery 2016
PUBMED: 27231123; DOI: 10.1158/2159-8290.CD-15-1442
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Multilevel models improve precision and speed of IC50 estimates.
Pharmacogenomics 2016;17;7;691-700
PUBMED: 27180993; PMC: 6455999; DOI: 10.2217/pgs.16.15
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Exploitation of the Apoptosis-Primed State of MYCN-Amplified Neuroblastoma to Develop a Potent and Specific Targeted Therapy Combination.
Cancer cell 2016;29;2;159-72
PUBMED: 26859456; DOI: 10.1016/j.ccell.2016.01.002
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Integration of genomic, transcriptomic and proteomic data identifies two biologically distinct subtypes of invasive lobular breast cancer.
Scientific reports 2016;6;18517
PUBMED: 26729235; PMC: 4700448; DOI: 10.1038/srep18517
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Pharmacogenomic agreement between two cancer cell line data sets.
Nature 2015;528;7580;84-7
PUBMED: 26570998; PMC: 6343827; DOI: 10.1038/nature15736
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LIM kinase inhibitors disrupt mitotic microtubule organization and impair tumor cell proliferation.
Oncotarget 2015;6;36;38469-86
PUBMED: 26540348; DOI: 10.18632/oncotarget.6288
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Potent organo-osmium compound shifts metabolism in epithelial ovarian cancer cells.
Proceedings of the National Academy of Sciences of the United States of America 2015;112;29;E3800-5
PUBMED: 26162681; PMC: 4517206; DOI: 10.1073/pnas.1500925112
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Prospective derivation of a living organoid biobank of colorectal cancer patients.
Cell 2015;161;4;933-45
PUBMED: 25957691; PMC: 6428276; DOI: 10.1016/j.cell.2015.03.053
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A Semi-Supervised Approach for Refining Transcriptional Signatures of Drug Response and Repositioning Predictions.
PloS one 2015;10;10;e0139446
PUBMED: 26452147; PMC: 4599732; DOI: 10.1371/journal.pone.0139446
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BRAF/NRAS wild-type melanoma, NF1 status and sensitivity to trametinib.
Pigment cell & melanoma research 2015;28;1;117-9
PUBMED: 25243813; PMC: 4296225; DOI: 10.1111/pcmr.12316
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Combinations of PARP Inhibitors with Temozolomide Drive PARP1 Trapping and Apoptosis in Ewing's Sarcoma.
PloS one 2015;10;10;e0140988
PUBMED: 26505995; PMC: 4624427; DOI: 10.1371/journal.pone.0140988
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What role could organoids play in the personalization of cancer treatment?
Pharmacogenomics 2015;16;14;1523-6
PUBMED: 26485224; DOI: 10.2217/pgs.15.114
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Fast randomization of large genomic datasets while preserving alteration counts.
Bioinformatics (Oxford, England) 2014;30;17;i617-23
PUBMED: 25161255; PMC: 4147926; DOI: 10.1093/bioinformatics/btu474
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The evolving role of cancer cell line-based screens to define the impact of cancer genomes on drug response.
Current opinion in genetics & development 2014;24;114-9
PUBMED: 24607840; PMC: 4003351; DOI: 10.1016/j.gde.2013.12.002
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Mcl-1 and FBW7 control a dominant survival pathway underlying HDAC and Bcl-2 inhibitor synergy in squamous cell carcinoma.
Cancer discovery 2013;3;3;324-37
PUBMED: 23274910; PMC: 3595349; DOI: 10.1158/2159-8290.CD-12-0417
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Targeting MYCN in neuroblastoma by BET bromodomain inhibition.
Cancer discovery 2013;3;3;308-23
PUBMED: 23430699; PMC: 3672953; DOI: 10.1158/2159-8290.CD-12-0418
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VS-5584, a novel and highly selective PI3K/mTOR kinase inhibitor for the treatment of cancer.
Molecular cancer therapeutics 2013;12;2;151-61
PUBMED: 23270925; PMC: 3588144; DOI: 10.1158/1535-7163.MCT-12-0466
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Genomics of Drug Sensitivity in Cancer (GDSC): a resource for therapeutic biomarker discovery in cancer cells.
Nucleic acids research 2013;41;Database issue;D955-61
PUBMED: 23180760; PMC: 3531057; DOI: 10.1093/nar/gks1111
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Machine learning prediction of cancer cell sensitivity to drugs based on genomic and chemical properties.
PloS one 2013;8;4;e61318
PUBMED: 23646105; PMC: 3640019; DOI: 10.1371/journal.pone.0061318
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MED12 controls the response to multiple cancer drugs through regulation of TGF-β receptor signaling.
Cell 2012;151;5;937-50
PUBMED: 23178117; PMC: 3672971; DOI: 10.1016/j.cell.2012.10.035
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Systematic identification of genomic markers of drug sensitivity in cancer cells.
Nature 2012;483;7391;570-5
PUBMED: 22460902; PMC: 3349233; DOI: 10.1038/nature11005
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Exploiting genetic complexity in cancer to improve therapeutic strategies.
Drug discovery today 2012;17;5-6;188-93
PUBMED: 22342219; PMC: 3672976; DOI: 10.1016/j.drudis.2012.01.025
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A mitotic function for the high-mobility group protein HMG20b regulated by its interaction with the BRC repeats of the BRCA2 tumor suppressor.
Oncogene 2011;30;30;3360-9
PUBMED: 21399666; PMC: 3145889; DOI: 10.1038/onc.2011.55
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UBE2S elongates ubiquitin chains on APC/C substrates to promote mitotic exit.
Nature cell biology 2009;11;11;1363-9
PUBMED: 19820702; PMC: 2875106; DOI: 10.1038/ncb1983
-
Wild-type and mutant B-RAF activate C-RAF through distinct mechanisms involving heterodimerization.
Molecular cell 2005;20;6;963-9
PUBMED: 16364920; DOI: 10.1016/j.molcel.2005.10.022
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Mutations of C-RAF are rare in human cancer because C-RAF has a low basal kinase activity compared with B-RAF.
Cancer research 2005;65;21;9719-26
PUBMED: 16266992; DOI: 10.1158/0008-5472.CAN-05-1683
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Guilty as charged: B-RAF is a human oncogene.
Cancer cell 2004;6;4;313-9
PUBMED: 15488754; DOI: 10.1016/j.ccr.2004.09.022
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Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF.
Cell 2004;116;6;855-67
PUBMED: 15035987; DOI: 10.1016/s0092-8674(04)00215-6
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ETV6-NTRK3 transformation requires insulin-like growth factor 1 receptor signaling and is associated with constitutive IRS-1 tyrosine phosphorylation.
Oncogene 2002;21;37;5684-95
PUBMED: 12173038; DOI: 10.1038/sj.onc.1205669
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Mutations of the BRAF gene in human cancer.
Nature 2002;417;6892;949-54
PUBMED: 12068308; DOI: 10.1038/nature00766
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The chimeric protein tyrosine kinase ETV6-NTRK3 requires both Ras-Erk1/2 and PI3-kinase-Akt signaling for fibroblast transformation.
Cancer research 2001;61;24;8909-16
PUBMED: 11751416