New insights into RAS biology reinvigorate interest in mathematical modeling of RAS signaling
Abstract
RAS is the most frequently mutated gene across human cancers, but developing inhibitors of mutant RAS has proven to be challenging. Given the difficulties of targeting RAS directly, drugs that impact the other components of pathways where mutant RAS operates may potentially be effective. However, the system-level features, including different localizations of RAS isoforms, competition between downstream effectors, and interlocking feedback and feed-forward loops, must be understood to fully grasp the opportunities and limitations of inhibiting specific targets. Mathematical modeling can help us discern the system-level impacts of these features in normal and cancer cells. New technologies enable the acquisition of experimental data that will facilitate development of realistic models of oncogenic RAS behavior. In light of the wealth of empirical data accumulated over decades of study and the advancement of experimental methods for gathering new data, modelers now have the opportunity to advance progress toward realization of targeted treatment for mutant RAS-driven cancers.
- Authors:
-
- Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
- Univ. College Dublin (United Kingdom)
- Northern Arizona Univ., Flagstaff, AZ (United States)
- Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Univ. of New Mexico Comprehensive Cancer Center, Albuquerque, NM (United States)
- Publication Date:
- Research Org.:
- Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)
- Sponsoring Org.:
- USDOE
- OSTI Identifier:
- 1425769
- Report Number(s):
- LA-UR-17-31291
Journal ID: ISSN 1044-579X
- Grant/Contract Number:
- AC52-06NA25396
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Seminars in Cancer Biology
- Additional Journal Information:
- Journal Volume: 54; Journal ID: ISSN 1044-579X
- Publisher:
- Elsevier
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; Biological Science; RAS; ERK cascade; Mechanistic modeling; Mathematical modeling; Systems biology
Citation Formats
Erickson, Keesha E., Rukhlenko, Oleksii S., Posner, Richard G., Hlavacek, William S., and Kholodenko, Boris N. New insights into RAS biology reinvigorate interest in mathematical modeling of RAS signaling. United States: N. p., 2018.
Web. doi:10.1016/j.semcancer.2018.02.008.
Erickson, Keesha E., Rukhlenko, Oleksii S., Posner, Richard G., Hlavacek, William S., & Kholodenko, Boris N. New insights into RAS biology reinvigorate interest in mathematical modeling of RAS signaling. United States. https://doi.org/10.1016/j.semcancer.2018.02.008
Erickson, Keesha E., Rukhlenko, Oleksii S., Posner, Richard G., Hlavacek, William S., and Kholodenko, Boris N. Mon .
"New insights into RAS biology reinvigorate interest in mathematical modeling of RAS signaling". United States. https://doi.org/10.1016/j.semcancer.2018.02.008. https://www.osti.gov/servlets/purl/1425769.
@article{osti_1425769,
title = {New insights into RAS biology reinvigorate interest in mathematical modeling of RAS signaling},
author = {Erickson, Keesha E. and Rukhlenko, Oleksii S. and Posner, Richard G. and Hlavacek, William S. and Kholodenko, Boris N.},
abstractNote = {RAS is the most frequently mutated gene across human cancers, but developing inhibitors of mutant RAS has proven to be challenging. Given the difficulties of targeting RAS directly, drugs that impact the other components of pathways where mutant RAS operates may potentially be effective. However, the system-level features, including different localizations of RAS isoforms, competition between downstream effectors, and interlocking feedback and feed-forward loops, must be understood to fully grasp the opportunities and limitations of inhibiting specific targets. Mathematical modeling can help us discern the system-level impacts of these features in normal and cancer cells. New technologies enable the acquisition of experimental data that will facilitate development of realistic models of oncogenic RAS behavior. In light of the wealth of empirical data accumulated over decades of study and the advancement of experimental methods for gathering new data, modelers now have the opportunity to advance progress toward realization of targeted treatment for mutant RAS-driven cancers.},
doi = {10.1016/j.semcancer.2018.02.008},
journal = {Seminars in Cancer Biology},
number = ,
volume = 54,
place = {United States},
year = {Mon Mar 05 00:00:00 EST 2018},
month = {Mon Mar 05 00:00:00 EST 2018}
}
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Figure 1: The RAS activation cycle. RAS can bind either GTP or GDP, and is active when bound to GTP. In the active configuration, it is able to interact with downstream effectors. RAS activation/deactivation can occur through multiple processes. Processes of interest are labeled with circled numbers: 1 shows freemore »
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Works referenced in this record:
Dragging Ras Back in the Ring
journal, March 2014
- Stephen, Andrew G.; Esposito, Dominic; Bagni, Rachel K.
- Cancer Cell, Vol. 25, Issue 3
Farnesyltransferase-Mediated Delivery of a Covalent Inhibitor Overcomes Alternative Prenylation to Mislocalize K-Ras
journal, June 2017
- Novotny, Chris J.; Hamilton, Gregory L.; McCormick, Frank
- ACS Chemical Biology, Vol. 12, Issue 7
An open-label, phase II study of tipifarnib for the treatment of HRAS mutant solid tumors, including squamous cell carcinomas of the head and neck.
journal, May 2017
- Ho, Alan Loh; Chau, Nicole Grace; Wong, Deborah Jean Lee
- Journal of Clinical Oncology, Vol. 35, Issue 15_suppl
A cytoplasmic protein stimulates normal N-ras p21 GTPase, but does not affect oncogenic mutants
journal, October 1987
- Trahey, M.; McCormick, F.
- Science, Vol. 238, Issue 4826
Monitoring the GAP catalyzed H-Ras GTPase reaction at atomic resolution in real time
journal, July 2001
- Allin, Christoph; Ahmadian, Mohammad Reza; Wittinghofer, Alfred
- Proceedings of the National Academy of Sciences, Vol. 98, Issue 14
Ras Catalyzes GTP Hydrolysis by Shifting Negative Charges from γ - to β -Phosphate As Revealed by Time-Resolved FTIR Difference Spectroscopy †
journal, March 2001
- Allin, Christoph; Gerwert, Klaus
- Biochemistry, Vol. 40, Issue 10
Confirmation of the arginine-finger hypothesis for the GAP-stimulated GTP-hydrolysis reaction of Ras
journal, September 1997
- Ahmadian, Mohammad Reza; Stege, Patricia; Scheffzek, Klaus
- Nature Structural Biology, Vol. 4, Issue 9
Ras superfamily GEFs and GAPs: validated and tractable targets for cancer therapy?
journal, November 2010
- Vigil, Dominico; Cherfils, Jacqueline; Rossman, Kent L.
- Nature Reviews Cancer, Vol. 10, Issue 12
Signal-transducing protein phosphorylation cascades mediated by Ras/Rho proteins in the mammalian cell: the potential for multiplex signalling
journal, September 1996
- Denhardt, David T.
- Biochemical Journal, Vol. 318, Issue 3
GEFs and GAPs: Critical Elements in the Control of Small G Proteins
journal, June 2007
- Bos, Johannes L.; Rehmann, Holger; Wittinghofer, Alfred
- Cell, Vol. 129, Issue 5
The RasGAP Gene, RASAL2, Is a Tumor and Metastasis Suppressor
journal, September 2013
- McLaughlin, Sara Koenig; Olsen, Sarah Naomi; Dake, Benjamin
- Cancer Cell, Vol. 24, Issue 3
Inactivation of RASA1 promotes melanoma tumorigenesis via R-Ras activation
journal, March 2016
- Sung, Hyeran; Kanchi, Krishna L.; Wang, Xue
- Oncotarget, Vol. 7, Issue 17
Signal processing at the Ras circuit: what shapes Ras activation patterns?
journal, June 2004
- Kholodenko, B. N.; Demin, O. V.; Markevich, N. I.
- Systems Biology, Vol. 1, Issue 1
The RalGEF-Ral Effector Signaling Network: The Road Less Traveled for Anti-Ras Drug Discovery
journal, March 2011
- Neel, N. F.; Martin, T. D.; Stratford, J. K.
- Genes & Cancer, Vol. 2, Issue 3
KRAS Engages AGO2 to Enhance Cellular Transformation
journal, February 2016
- Shankar, Sunita; Pitchiaya, Sethuramasundaram; Malik, Rohit
- Cell Reports, Vol. 14, Issue 6
Ras effectors and their role in mitogenesis and oncogenesis
journal, August 1997
- Joneson, T.; Bar-Sagi, D.
- Journal of Molecular Medicine, Vol. 75, Issue 8
GTP-Dependent K-Ras Dimerization
journal, July 2015
- Muratcioglu, Serena; Chavan, Tanmay S.; Freed, Benjamin C.
- Structure, Vol. 23, Issue 7
A Comprehensive Survey of Ras Mutations in Cancer
journal, May 2012
- Prior, I. A.; Lewis, P. D.; Mattos, C.
- Cancer Research, Vol. 72, Issue 10
Functional Specificity of Ras Isoforms: So Similar but So Different
journal, March 2011
- Castellano, E.; Santos, E.
- Genes & Cancer, Vol. 2, Issue 3
Targeting mutant NRAS signaling pathways in melanoma
journal, May 2016
- Vu, Ha Linh; Aplin, Andrew E.
- Pharmacological Research, Vol. 107
The Cancer Genome Atlas Pan-Cancer analysis project
journal, September 2013
- Weinstein, John N.; Collisson, Eric A.; Mills, Gordon B.
- Nature Genetics, Vol. 45, Issue 10
Mechanistic modeling to investigate signaling by oncogenic Ras mutants
journal, July 2011
- Stites, Edward C.; Ravichandran, Kodi S.
- WIREs Systems Biology and Medicine, Vol. 4, Issue 1
Differential feedback regulation of the MAPK cascade underlies the quantitative differences in EGF and NGF signalling in PC12 cells
journal, October 2000
- Brightman, Frances A.; Fell, David A.
- FEBS Letters, Vol. 482, Issue 3
Computational modeling of the dynamics of the MAP kinase cascade activated by surface and internalized EGF receptors
journal, April 2002
- Schoeberl, Birgit; Eichler-Jonsson, Claudia; Gilles, Ernst Dieter
- Nature Biotechnology, Vol. 20, Issue 4
Quantification of Short Term Signaling by the Epidermal Growth Factor Receptor
journal, October 1999
- Kholodenko, Boris N.; Demin, Oleg V.; Moehren, Gisela
- Journal of Biological Chemistry, Vol. 274, Issue 42
Computational modelling of the receptor-tyrosine-kinase-activated MAPK pathway
journal, November 2005
- Orton, Richard J.; Sturm, Oliver E.; Vyshemirsky, Vladislav
- Biochemical Journal, Vol. 392, Issue 2
Network Analysis of Oncogenic Ras Activation in Cancer
journal, October 2007
- Stites, E. C.; Trampont, P. C.; Ma, Z.
- Science, Vol. 318, Issue 5849
Computational modelling of cancerous mutations in the EGFR/ERK signalling pathway
journal, October 2009
- Orton, Richard J.; Adriaens, Michiel E.; Gormand, Amelie
- BMC Systems Biology, Vol. 3, Issue 1
Cooperation between Noncanonical Ras Network Mutations
journal, January 2015
- Stites, Edward C.; Trampont, Paul C.; Haney, Lisa B.
- Cell Reports, Vol. 10, Issue 3
Signalling ballet in space and time
journal, June 2010
- Kholodenko, Boris N.; Hancock, John F.; Kolch, Walter
- Nature Reviews Molecular Cell Biology, Vol. 11, Issue 6
Allosteric modulation of Ras positions Q61 for a direct role in catalysis
journal, March 2010
- Buhrman, G.; Holzapfel, G.; Fetics, S.
- Proceedings of the National Academy of Sciences, Vol. 107, Issue 11
Effect of KRAS Oncogene Substitutions on Protein Behavior: Implications for Signaling and Clinical Outcome
journal, January 2012
- Ihle, Nathan T.; Byers, Lauren A.; Kim, Edward S.
- JNCI: Journal of the National Cancer Institute, Vol. 104, Issue 3
Kinetics of interaction of nucleotides with nucleotide-free H-ras p21
journal, June 1990
- John, Jacob; Sohmen, Roland; Feuerstein, Juergen
- Biochemistry, Vol. 29, Issue 25
Structural Evidence for Feedback Activation by Ras·GTP of the Ras-Specific Nucleotide Exchange Factor SOS
journal, March 2003
- Margarit, S. Mariana; Sondermann, Holger; Hall, Brian E.
- Cell, Vol. 112, Issue 5
Germline KRAS mutations cause aberrant biochemical and physical properties leading to developmental disorders
journal, December 2010
- Gremer, Lothar; Merbitz-Zahradnik, Torsten; Dvorsky, Radovan
- Human Mutation, Vol. 32, Issue 1
Duplication of Glu37 in the switch I region of HRAS impairs effector/GAP binding and underlies Costello syndrome by promoting enhanced growth factor-dependent MAPK and AKT activation
journal, December 2009
- Gremer, Lothar; De Luca, Alessandro; Merbitz-Zahradnik, Torsten
- Human Molecular Genetics, Vol. 19, Issue 5
Diverging gain-of-function mechanisms of two novel KRAS mutations associated with Noonan and cardio-facio-cutaneous syndromes
journal, October 2012
- Cirstea, I. C.; Gremer, L.; Dvorsky, R.
- Human Molecular Genetics, Vol. 22, Issue 2
Mutation analysis in Costello syndrome: functional and structural characterization of theHRASp.Lys117Arg mutation
journal, February 2008
- Denayer, Ellen; Parret, Annabel; Chmara, Magdalena
- Human Mutation, Vol. 29, Issue 2
Structure‐energy‐based predictions and network modelling of
RAS
opathy and cancer missense mutations
journal, May 2014
- Kiel, Christina; Serrano, Luis
- Molecular Systems Biology, Vol. 10, Issue 5
NMR spectroscopy brings invisible protein states into focus
journal, October 2009
- Baldwin, Andrew J.; Kay, Lewis E.
- Nature Chemical Biology, Vol. 5, Issue 11
Observing biological dynamics at atomic resolution using NMR
journal, December 2009
- Mittermaier, Anthony K.; Kay, Lewis E.
- Trends in Biochemical Sciences, Vol. 34, Issue 12
Cell signaling, post-translational protein modifications and NMR spectroscopy
journal, September 2012
- Theillet, Francois-Xavier; Smet-Nocca, Caroline; Liokatis, Stamatios
- Journal of Biomolecular NMR, Vol. 54, Issue 3
NMR-based functional profiling of RASopathies and oncogenic RAS mutations
journal, March 2013
- Smith, M. J.; Neel, B. G.; Ikura, M.
- Proceedings of the National Academy of Sciences, Vol. 110, Issue 12
Comprehensive Binary Interaction Mapping of SH2 Domains via Fluorescence Polarization Reveals Novel Functional Diversification of ErbB Receptors
journal, September 2012
- Hause, Ronald J.; Leung, Kin K.; Barkinge, John L.
- PLoS ONE, Vol. 7, Issue 9
Quantifying protein–protein interactions in high throughput using protein domain microarrays
journal, April 2010
- Kaushansky, Alexis; Allen, John E.; Gordus, Andrew
- Nature Protocols, Vol. 5, Issue 4
Quantifying domain-ligand affinities and specificities by high-throughput holdup assay
journal, June 2015
- Vincentelli, Renaud; Luck, Katja; Poirson, Juline
- Nature Methods, Vol. 12, Issue 8
Measuring the sequence-affinity landscape of antibodies with massively parallel titration curves
journal, December 2016
- Adams, Rhys M.; Mora, Thierry; Walczak, Aleksandra M.
- eLife, Vol. 5
Determination of binding affinity upon mutation for type I dockerin–cohesin complexes from
C
lostridium thermocellum
and
C
lostridium cellulolyticum
using deep sequencing
journal, October 2016
- Kowalsky, Caitlin A.; Whitehead, Timothy A.
- Proteins: Structure, Function, and Bioinformatics, Vol. 84, Issue 12
Use of Mechanistic Models to Integrate and Analyze Multiple Proteomic Datasets
journal, April 2015
- Stites, Edward C.; Aziz, Meraj; Creamer, Matthew S.
- Biophysical Journal, Vol. 108, Issue 7
Ras activation by SOS: Allosteric regulation by altered fluctuation dynamics
journal, July 2014
- Iversen, Lars; Tu, Hsiung-Lin; Lin, Wan-Chen
- Science, Vol. 345, Issue 6192
The Coming Age of Complete, Accurate, and Ubiquitous Proteomes
journal, February 2013
- Mann, Matthias; Kulak, Nils A.; Nagaraj, Nagarjuna
- Molecular Cell, Vol. 49, Issue 4
Deep proteome and transcriptome mapping of a human cancer cell line
journal, January 2011
- Nagaraj, Nagarjuna; Wisniewski, Jacek R.; Geiger, Tamar
- Molecular Systems Biology, Vol. 7, Issue 1
Global quantification of mammalian gene expression control
journal, May 2011
- Schwanhäusser, Björn; Busse, Dorothea; Li, Na
- Nature, Vol. 473, Issue 7347
Minimal, encapsulated proteomic-sample processing applied to copy-number estimation in eukaryotic cells
journal, February 2014
- Kulak, Nils A.; Pichler, Garwin; Paron, Igor
- Nature Methods, Vol. 11, Issue 3
Mass-spectrometric exploration of proteome structure and function
journal, September 2016
- Aebersold, Ruedi; Mann, Matthias
- Nature, Vol. 537, Issue 7620
Quantification of ErbB Network Proteins in Three Cell Types Using Complementary Approaches Identifies Cell-General and Cell-Type-Specific Signaling Proteins
journal, December 2013
- Kiel, Christina; Ebhardt, H. Alexander; Burnier, Julia
- Journal of Proteome Research, Vol. 13, Issue 1
Antibody-free, targeted mass-spectrometric approach for quantification of proteins at low picogram per milliliter levels in human plasma/serum
journal, September 2012
- Shi, T.; Fillmore, T. L.; Sun, X.
- Proceedings of the National Academy of Sciences, Vol. 109, Issue 38
Conservation of protein abundance patterns reveals the regulatory architecture of the EGFR-MAPK pathway
journal, July 2016
- Shi, Tujin; Niepel, Mario; McDermott, Jason E.
- Science Signaling, Vol. 9, Issue 436
Phosphoproteomics Identifies Oncogenic Ras Signaling Targets and Their Involvement in Lung Adenocarcinomas
journal, May 2011
- Sudhir, Putty-Reddy; Hsu, Chia-Lang; Wang, Mei-Jung
- PLoS ONE, Vol. 6, Issue 5
Systems-wide Analysis of K-Ras, Cdc42, and PAK4 Signaling by Quantitative Phosphoproteomics
journal, August 2013
- Gnad, Florian; Young, Amy; Zhou, Wei
- Molecular & Cellular Proteomics, Vol. 12, Issue 8
Akt-RSK-S6 Kinase Signaling Networks Activated by Oncogenic Receptor Tyrosine Kinases
journal, August 2010
- Moritz, A.; Li, Y.; Guo, A.
- Science Signaling, Vol. 3, Issue 136
Genome-Scale CRISPR-Cas9 Knockout Screening in Human Cells
journal, December 2013
- Shalem, Ophir; Sanjana, Neville E.; Hartenian, Ella
- Science, Vol. 343, Issue 6166, p. 84-87
Genetic Screens in Human Cells Using the CRISPR-Cas9 System
journal, December 2013
- Wang, Tim; Wei, Jenny J.; Sabatini, David M.
- Science, Vol. 343, Issue 6166
Multiplex Genome Engineering Using CRISPR/Cas Systems
journal, January 2013
- Cong, L.; Ran, F. A.; Cox, D.
- Science, Vol. 339, Issue 6121, p. 819-823
RNA-Guided Human Genome Engineering via Cas9
journal, January 2013
- Mali, P.; Yang, L.; Esvelt, K. M.
- Science, Vol. 339, Issue 6121, p. 823-826
Genome-scale transcriptional activation by an engineered CRISPR-Cas9 complex
journal, December 2014
- Konermann, Silvana; Brigham, Mark D.; Trevino, Alexandro E.
- Nature, Vol. 517, Issue 7536
Gene Essentiality Profiling Reveals Gene Networks and Synthetic Lethal Interactions with Oncogenic Ras
journal, February 2017
- Wang, Tim; Yu, Haiyan; Hughes, Nicholas W.
- Cell, Vol. 168, Issue 5
A Phosphatase Holoenzyme Comprised of Shoc2/Sur8 and the Catalytic Subunit of PP1 Functions as an M-Ras Effector to Modulate Raf Activity
journal, April 2006
- Rodriguez-Viciana, Pablo; Oses-Prieto, Juan; Burlingame, Alma
- Molecular Cell, Vol. 22, Issue 2
An MRAS, SHOC2, and SCRIB Complex Coordinates ERK Pathway Activation with Polarity and Tumorigenic Growth
journal, December 2013
- Young, Lucy C.; Hartig, Nicole; Muñoz-Alegre, Marta
- Molecular Cell, Vol. 52, Issue 5
The Spread of Ras Activity Triggered by Activation of a Single Dendritic Spine
journal, July 2008
- Harvey, C. D.; Yasuda, R.; Zhong, H.
- Science, Vol. 321, Issue 5885
Spatially distributed cell signalling
journal, October 2009
- Kholodenko, Boris N.
- FEBS Letters, Vol. 583, Issue 24
The topology design principles that determine the spatiotemporal dynamics of G-protein cascades
journal, January 2012
- Tsyganov, Mikhail A.; Kolch, Walter; Kholodenko, Boris N.
- Molecular BioSystems, Vol. 8, Issue 3
Signalling over a distance: gradient patterns and phosphorylation waves within single cells
journal, September 2010
- Muñoz-García, Javier; Kholodenko, Boris N.
- Biochemical Society Transactions, Vol. 38, Issue 5
Targeting mutant RAS in patient-derived colorectal cancer organoids by combinatorial drug screening
journal, November 2016
- Verissimo, Carla S.; Overmeer, René M.; Ponsioen, Bas
- eLife, Vol. 5
A genetically encoded fluorescent sensor of ERK activity
journal, December 2008
- Harvey, Christopher D.; Ehrhardt, Anka G.; Cellurale, Cristina
- Proceedings of the National Academy of Sciences, Vol. 105, Issue 49
Frequency-Modulated Pulses of ERK Activity Transmit Quantitative Proliferation Signals
journal, January 2013
- Albeck, John G.; Mills, Gordon B.; Brugge, Joan S.
- Molecular Cell, Vol. 49, Issue 2
Frequency modulation of ERK activation dynamics rewires cell fate
journal, November 2015
- Ryu, Hyunryul; Chung, Minhwan; Dobrzyński, Maciej
- Molecular Systems Biology, Vol. 11, Issue 11
Optimization of ERK Activity Biosensors for both Ratiometric and Lifetime FRET Measurements
journal, January 2014
- Vandame, Pauline; Spriet, Corentin; Riquet, Franck
- Sensors, Vol. 14, Issue 1
High-Sensitivity Measurements of Multiple Kinase Activities in Live Single Cells
journal, June 2014
- Regot, Sergi; Hughey, Jacob J.; Bajar, Bryce T.
- Cell, Vol. 157, Issue 7
Using Optogenetics to Interrogate the Dynamic Control of Signal Transmission by the Ras/Erk Module
journal, December 2013
- Toettcher, Jared E.; Weiner, Orion D.; Lim, Wendell A.
- Cell, Vol. 155, Issue 6
Spatiotemporal control of cell signalling using a light-switchable protein interaction
journal, September 2009
- Levskaya, Anselm; Weiner, Orion D.; Lim, Wendell A.
- Nature, Vol. 461, Issue 7266
Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr–Abl positive cells
journal, May 1996
- Druker, Brian J.; Tamura, Shu; Buchdunger, Elisabeth
- Nature Medicine, Vol. 2, Issue 5
Specific Targeted Therapy of Chronic Myelogenous Leukemia with Imatinib
journal, July 2003
- Deininger, Michael W. N.; Druker, Brian J.
- Pharmacological Reviews, Vol. 55, Issue 3
Inhibition of Mutated, Activated BRAF in Metastatic Melanoma
journal, August 2010
- Flaherty, Keith T.; Puzanov, Igor; Kim, Kevin B.
- New England Journal of Medicine, Vol. 363, Issue 9
Mutations of the BRAF gene in human cancer
journal, June 2002
- Davies, Helen; Bignell, Graham R.; Cox, Charles
- Nature, Vol. 417, Issue 6892
FDA Drug Approval Summary: Gefitinib (ZD1839) (Iressa®) Tablets
journal, August 2003
- Cohen, Martin H.; Williams, Grant A.; Sridhara, Rajeshwari
- The Oncologist, Vol. 8, Issue 4
U.S. Food and Drug Administration Approval Summary: Erlotinib for the First-Line Treatment of Metastatic Non-Small Cell Lung Cancer With Epidermal Growth Factor Receptor Exon 19 Deletions or Exon 21 (L858R) Substitution Mutations
journal, May 2014
- Khozin, Sean; Blumenthal, Gideon M.; Jiang, Xiaoping
- The Oncologist, Vol. 19, Issue 7
Afatinib: A Review of Its Use in the Treatment of Advanced Non-Small Cell Lung Cancer
journal, January 2014
- Keating, Gillian M.
- Drugs, Vol. 74, Issue 2
FDA-approved small-molecule kinase inhibitors
journal, July 2015
- Wu, Peng; Nielsen, Thomas E.; Clausen, Mads H.
- Trends in Pharmacological Sciences, Vol. 36, Issue 7
Inhibition of Lapatinib-Induced Kinome Reprogramming in ERBB2-Positive Breast Cancer by Targeting BET Family Bromodomains
journal, April 2015
- Stuhlmiller, Timothy J.; Miller, Samantha M.; Zawistowski, Jon S.
- Cell Reports, Vol. 11, Issue 3
Improved Overall Survival in Melanoma with Combined Dabrafenib and Trametinib
journal, January 2015
- Robert, Caroline; Karaszewska, Boguslawa; Schachter, Jacob
- New England Journal of Medicine, Vol. 372, Issue 1
2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial
journal, January 2007
- Smith, Ian; Procter, Marion; Gelber, Richard D.
- The Lancet, Vol. 369, Issue 9555
Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial
journal, August 2010
- Bang, Yung-Jue; Van Cutsem, Eric; Feyereislova, Andrea
- The Lancet, Vol. 376, Issue 9742
Small-molecule kinase inhibitors: an analysis of FDA-approved drugs
journal, January 2016
- Wu, Peng; Nielsen, Thomas E.; Clausen, Mads H.
- Drug Discovery Today, Vol. 21, Issue 1
Drugging the undruggable RAS: Mission Possible?
journal, October 2014
- Cox, Adrienne D.; Fesik, Stephen W.; Kimmelman, Alec C.
- Nature Reviews Drug Discovery, Vol. 13, Issue 11
K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions
journal, November 2013
- Ostrem, Jonathan M.; Peters, Ulf; Sos, Martin L.
- Nature, Vol. 503, Issue 7477
Selective Inhibition of Oncogenic KRAS Output with Small Molecules Targeting the Inactive State
journal, January 2016
- Patricelli, M. P.; Janes, M. R.; Li, L. -S.
- Cancer Discovery, Vol. 6, Issue 3
Identification of pyrazolopyridazinones as PDEδ inhibitors
journal, April 2016
- Papke, Björn; Murarka, Sandip; Vogel, Holger A.
- Nature Communications, Vol. 7, Issue 1
Small molecule inhibition of the KRAS–PDEδ interaction impairs oncogenic KRAS signalling
journal, May 2013
- Zimmermann, Gunther; Papke, Björn; Ismail, Shehab
- Nature, Vol. 497, Issue 7451
Small-molecule inhibition of APT1 affects Ras localization and signaling
journal, April 2010
- Dekker, Frank J.; Rocks, Oliver; Vartak, Nachiket
- Nature Chemical Biology, Vol. 6, Issue 6
Cancer stem cell drugs target K-ras signaling in a stemness context
journal, March 2016
- Najumudeen, A. K.; Jaiswal, A.; Lectez, B.
- Oncogene, Vol. 35, Issue 40
Cancer drug resistance: an evolving paradigm
journal, September 2013
- Holohan, Caitriona; Van Schaeybroeck, Sandra; Longley, Daniel B.
- Nature Reviews Cancer, Vol. 13, Issue 10
Circumventing Cancer Drug Resistance in the Era of Personalized Medicine
journal, February 2012
- Garraway, Levi A.; Jänne, Pasi A.
- Cancer Discovery, Vol. 2, Issue 3
Acquired Resistance of Lung Adenocarcinomas to Gefitinib or Erlotinib Is Associated with a Second Mutation in the EGFR Kinase Domain
journal, February 2005
- Pao, William; Miller, Vincent A.; Politi, Katerina A.
- PLoS Medicine, Vol. 2, Issue 3
Mechanisms of Resistance to RAF Inhibitors in Melanoma
journal, September 2011
- Aplin, Andrew E.; Kaplan, Fred M.; Shao, Yongping
- Journal of Investigative Dermatology, Vol. 131, Issue 9
Elevated CRAF as a Potential Mechanism of Acquired Resistance to BRAF Inhibition in Melanoma
journal, June 2008
- Montagut, Clara; Sharma, Sreenath V.; Shioda, Toshi
- Cancer Research, Vol. 68, Issue 12
COT drives resistance to RAF inhibition through MAP kinase pathway reactivation
journal, November 2010
- Johannessen, Cory M.; Boehm, Jesse S.; Kim, So Young
- Nature, Vol. 468, Issue 7326
Drug Resistance Resulting from Kinase Dimerization Is Rationalized by Thermodynamic Factors Describing Allosteric Inhibitor Effects
journal, September 2015
- Kholodenko, Boris N.
- Cell Reports, Vol. 12, Issue 11
Identification of Optimal Drug Combinations Targeting Cellular Networks: Integrating Phospho-Proteomics and Computational Network Analysis
journal, August 2010
- Iadevaia, Sergio; Lu, Yiling; Morales, Fabiana C.
- Cancer Research, Vol. 70, Issue 17
Insulin and Epidermal Growth Factor Receptors Regulate Distinct Pools of Grb2-SOS in the Control of Ras Activation
journal, July 1996
- Waters, Steven B.; Chen, Dong; Kao, Aimee W.
- Journal of Biological Chemistry, Vol. 271, Issue 30
Systems‐level interactions between insulin–EGF networks amplify mitogenic signaling
journal, January 2009
- Borisov, Nikolay; Aksamitiene, Edita; Kiyatkin, Anatoly
- Molecular Systems Biology, Vol. 5, Issue 1
Feedback activation of neurofibromin terminates growth factor-induced Ras activation
journal, February 2016
- Hennig, Anne; Markwart, Robby; Wolff, Katharina
- Cell Communication and Signaling, Vol. 14, Issue 1
A Mek1–Mek2 heterodimer determines the strength and duration of the Erk signal
journal, February 2009
- Catalanotti, Federica; Reyes, Gloria; Jesenberger, Veronika
- Nature Structural & Molecular Biology, Vol. 16, Issue 3
Identification of the mitogen-activated protein kinase phosphorylation sites on human Sos1 that regulate interaction with Grb2
journal, October 1996
- Corbalan-Garcia, S.; Yang, S. S.; Degenhardt, K. R.
- Molecular and Cellular Biology, Vol. 16, Issue 10
SOS Phosphorylation and Disassociation of the Grb2-SOS Complex by the ERK and JNK Signaling Pathways
journal, March 1996
- Chen§, Dong; Waters§, Steven B.; Holt, Kathleen H.
- Journal of Biological Chemistry, Vol. 271, Issue 11
Desensitization of Ras Activation by a Feedback Disassociation of the SOS-Grb2 Complex
journal, September 1995
- Waters, Steven B.; Holt, Kathleen H.; Ross, Susan E.
- Journal of Biological Chemistry, Vol. 270, Issue 36
Regulation of Raf-1 by Direct Feedback Phosphorylation
journal, January 2005
- Dougherty, Michele K.; Müller, Jürgen; Ritt, Daniel A.
- Molecular Cell, Vol. 17, Issue 2
Impact of Feedback Phosphorylation and Raf Heterodimerization on Normal and Mutant B-Raf Signaling
journal, November 2009
- Ritt, D. A.; Monson, D. M.; Specht, S. I.
- Molecular and Cellular Biology, Vol. 30, Issue 3
Mammalian Sprouty Proteins Inhibit Cell Growth and Differentiation by Preventing Ras Activation
journal, December 2001
- Gross, Isabelle; Bassit, Bhramdeo; Benezra, Miriam
- Journal of Biological Chemistry, Vol. 276, Issue 49
Sprouty Proteins Are Targeted to Membrane Ruffles upon Growth Factor Receptor Tyrosine Kinase Activation
journal, October 2000
- Lim, Jormay; Wong, Esther Sook Miin; Ong, Siew Hwa
- Journal of Biological Chemistry, Vol. 275, Issue 42
The developing story of Sprouty and cancer
journal, April 2014
- Masoumi-Moghaddam, Samar; Amini, Afshin; Morris, David Lawson
- Cancer and Metastasis Reviews, Vol. 33, Issue 2-3
Sprouty proteins: multifaceted negative-feedback regulators of receptor tyrosine kinase signaling
journal, January 2006
- Mason, Jacqueline M.; Morrison, Debra J.; Albert Basson, M.
- Trends in Cell Biology, Vol. 16, Issue 1
Phosphorylation of Carboxyl-terminal Tyrosines Modulates the Specificity of Sprouty-2 Inhibition of Different Signaling Pathways
journal, March 2005
- Rubin, Chanan; Zwang, Yaara; Vaisman, Nora
- Journal of Biological Chemistry, Vol. 280, Issue 10
SPRY2 Is an Inhibitor of the Ras/Extracellular Signal-Regulated Kinase Pathway in Melanocytes and Melanoma Cells with Wild-Type
BRAF
but Not with the V599E Mutant
journal, August 2004
- Tsavachidou, Dimitra; Coleman, Mathew L.; Athanasiadis, Galene
- Cancer Research, Vol. 64, Issue 16
mSprouty2 inhibits FGF10-activated MAP kinase by differentially binding to upstream target proteins
journal, October 2002
- Tefft, D.; Lee, M.; Smith, S.
- American Journal of Physiology-Lung Cellular and Molecular Physiology, Vol. 283, Issue 4
Regulation of Ras Signaling Dynamics by Sos-Mediated Positive Feedback
journal, November 2006
- Boykevisch, Sean; Zhao, Chen; Sondermann, Holger
- Current Biology, Vol. 16, Issue 21
A Ras-induced conformational switch in the Ras activator Son of sevenless
journal, October 2006
- Freedman, T. S.; Sondermann, H.; Friedland, G. D.
- Proceedings of the National Academy of Sciences, Vol. 103, Issue 45
Structural Analysis of Autoinhibition in the Ras Activator Son of Sevenless
journal, October 2004
- Sondermann, Holger; Soisson, Stephen M.; Boykevisch, Sean
- Cell, Vol. 119, Issue 3
Negative feedback and ultrasensitivity can bring about oscillations in the mitogen-activated protein kinase cascades: Sustained oscillations in MAPK cascades
journal, March 2000
- Kholodenko, Boris N.
- European Journal of Biochemistry, Vol. 267, Issue 6
Digital Signaling and Hysteresis Characterize Ras Activation in Lymphoid Cells
journal, January 2009
- Das, Jayajit; Ho, Mary; Zikherman, Julie
- Cell, Vol. 136, Issue 2
Influence of node abundance on signaling network state and dynamics analyzed by mass cytometry
journal, January 2017
- Lun, Xiao-Kang; Zanotelli, Vito R. T.; Wade, James D.
- Nature Biotechnology, Vol. 35, Issue 2
Emergence of bimodal cell population responses from the interplay between analog single-cell signaling and protein expression noise
journal, August 2012
- Birtwistle, Marc R.; Rauch, Jens; Kiyatkin, Anatoly
- BMC Systems Biology, Vol. 6, Issue 1
Nonlinear signalling networks and cell-to-cell variability transform external signals into broadly distributed or bimodal responses
journal, September 2014
- Dobrzyński, Maciej; Nguyen, Lan K.; Birtwistle, Marc R.
- Journal of The Royal Society Interface, Vol. 11, Issue 98
Positive- and negative-feedback regulations coordinate the dynamic behavior of the Ras-Raf-MEK-ERK signal transduction pathway
journal, January 2009
- Shin, S. -Y.; Rath, O.; Choo, S. -M.
- Journal of Cell Science, Vol. 122, Issue 3
Relaxation oscillations and hierarchy of feedbacks in MAPK signaling
journal, January 2017
- Kochańczyk, Marek; Kocieniewski, Paweł; Kozłowska, Emilia
- Scientific Reports, Vol. 7, Issue 1
Effects of sequestration on signal transduction cascades
journal, March 2006
- Bluthgen, Nils; Bruggeman, Frank J.; Legewie, Stefan
- FEBS Journal, Vol. 273, Issue 5
Signaling switches and bistability arising from multisite phosphorylation in protein kinase cascades
journal, January 2004
- Markevich, Nick I.; Hoek, Jan B.; Kholodenko, Boris N.
- Journal of Cell Biology, Vol. 164, Issue 3
C-TAK1 Regulates Ras Signaling by Phosphorylating the MAPK Scaffold, KSR1
journal, November 2001
- Müller, Jürgen; Ory, Stéphane; Copeland, Terry
- Molecular Cell, Vol. 8, Issue 5
The RhoGEF GEF-H1 Is Required for Oncogenic RAS Signaling via KSR-1
journal, February 2014
- Cullis, Jane; Meiri, David; Sandi, Maria Jose
- Cancer Cell, Vol. 25, Issue 2
Cell Signaling by Receptor Tyrosine Kinases
journal, June 2010
- Lemmon, Mark A.; Schlessinger, Joseph
- Cell, Vol. 141, Issue 7
Long‐range signaling by phosphoprotein waves arising from bistability in protein kinase cascades
journal, January 2006
- Markevich, Nick I.; Tsyganov, Mikhail A.; Hoek, Jan B.
- Molecular Systems Biology, Vol. 2, Issue 1
Scaffolding Protein Grb2-associated Binder 1 Sustains Epidermal Growth Factor-induced Mitogenic and Survival Signaling by Multiple Positive Feedback Loops
journal, May 2006
- Kiyatkin, Anatoly; Aksamitiene, Edita; Markevich, Nick I.
- Journal of Biological Chemistry, Vol. 281, Issue 29
Ras trafficking, localization and compartmentalized signalling
journal, April 2012
- Prior, Ian A.; Hancock, John F.
- Seminars in Cell & Developmental Biology, Vol. 23, Issue 2
Reversible intracellular translocation of KRas but not HRas in hippocampal neurons regulated by Ca2+/calmodulin
journal, July 2005
- Fivaz, Marc; Meyer, Tobias
- Journal of Cell Biology, Vol. 170, Issue 3
Regulating c-Ras function
journal, November 2001
- Kranenburg, Onno; Verlaan, Ingrid; Moolenaar, Wouter H.
- Current Biology, Vol. 11, Issue 23
Distinct Utilization of Effectors and Biological Outcomes Resulting from Site-Specific Ras Activation: Ras Functions in Lipid Rafts and Golgi Complex Are Dispensable for Proliferation and Transformation
journal, January 2006
- Matallanas, David; Sanz-Moreno, Victoria; Arozarena, Imanol
- Molecular and Cellular Biology, Vol. 26, Issue 1
KRas Localizes to the Plasma Membrane by Spatial Cycles of Solubilization, Trapping and Vesicular Transport
journal, April 2014
- Schmick, Malte; Vartak, Nachiket; Papke, Björn
- Cell, Vol. 157, Issue 2
The RAS-Effector Interface: Isoform-Specific Differences in the Effector Binding Regions
journal, December 2016
- Nakhaeizadeh, Hossein; Amin, Ehsan; Nakhaei-Rad, Saeideh
- PLOS ONE, Vol. 11, Issue 12
Signaling pathway models as biomarkers: Patient-specific simulations of JNK activity predict the survival of neuroblastoma patients
journal, December 2015
- Fey, D.; Halasz, M.; Dreidax, D.
- Science Signaling, Vol. 8, Issue 408
Optimization of Dosing for EGFR-Mutant Non-Small Cell Lung Cancer with Evolutionary Cancer Modeling
journal, July 2011
- Chmielecki, J.; Foo, J.; Oxnard, G. R.
- Science Translational Medicine, Vol. 3, Issue 90
Spatial Heterogeneity and Evolutionary Dynamics Modulate Time to Recurrence in Continuous and Adaptive Cancer Therapies
journal, January 2018
- Gallaher, Jill A.; Enriquez-Navas, Pedro M.; Luddy, Kimberly A.
- Cancer Research, Vol. 78, Issue 8
Exploiting evolutionary principles to prolong tumor control in preclinical models of breast cancer
journal, February 2016
- Enriquez-Navas, Pedro M.; Kam, Yoonseok; Das, Tuhin
- Science Translational Medicine, Vol. 8, Issue 327
A Multidisciplinary Model Predicts Clinical Response in Relapsed Multiple Myeloma
journal, December 2015
- Shain, Kenneth H.; Silva, Ariosto; Meads, Mark B.
- Blood, Vol. 126, Issue 23
Mathematical modeling of erythrocyte chimerism informs genetic intervention strategies for sickle cell disease
journal, July 2016
- Altrock, Philipp M.; Brendel, Christian; Renella, Raffaele
- American Journal of Hematology, Vol. 91, Issue 9
Mathematical Modeling of Cancer Immunotherapy and Its Synergy with Radiotherapy
journal, August 2016
- Serre, Raphael; Benzekry, Sebastien; Padovani, Laetitia
- Cancer Research, Vol. 76, Issue 17
Phase i trials in melanoma: A framework to translate preclinical findings to the clinic
journal, November 2016
- Kim, Eunjung; Rebecca, Vito W.; Smalley, Keiran S. M.
- European Journal of Cancer, Vol. 67
Systems biology and combination therapy in the quest for clinical efficacy
journal, August 2006
- Fitzgerald, Jonathan B.; Schoeberl, Birgit; Nielsen, Ulrik B.
- Nature Chemical Biology, Vol. 2, Issue 9
The National Cancer Institute ALMANAC: A Comprehensive Screening Resource for the Detection of Anticancer Drug Pairs with Enhanced Therapeutic Activity
journal, April 2017
- Holbeck, Susan L.; Camalier, Richard; Crowell, James A.
- Cancer Research, Vol. 77, Issue 13
Pharmacokinetics and Drug Interactions Determine Optimum Combination Strategies in Computational Models of Cancer Evolution
journal, May 2017
- Chakrabarti, Shaon; Michor, Franziska
- Cancer Research, Vol. 77, Issue 14
The dynamic control of signal transduction networks in cancer cells
journal, August 2015
- Kolch, Walter; Halasz, Melinda; Granovskaya, Marina
- Nature Reviews Cancer, Vol. 15, Issue 9
Kinetic Analysis by Fluorescence of the Interaction between Ras and the Catalytic Domain of the Guanine Nucleotide Exchange Factor Cdc25 Mm †
journal, May 1998
- Lenzen, Christian; Cool, Robbert H.; Prinz, Heino
- Biochemistry, Vol. 37, Issue 20
Fluorescence approaches to the study of the p21ras GTPase mechanism
journal, April 1991
- Eccleston, John F.; Moore, Keith J. M.; Brownbridge, Geoffrey G.
- Biochemical Society Transactions, Vol. 19, Issue 2
Biochemical and Structural Analysis of Common Cancer-Associated KRAS Mutations
journal, June 2015
- Hunter, J. C.; Manandhar, A.; Carrasco, M. A.
- Molecular Cancer Research, Vol. 13, Issue 9
Kinetic Mechanisms of Mutation-Dependent Harvey Ras Activation and Their Relevance for the Development of Costello Syndrome
journal, November 2013
- Wey, Michael; Lee, Jungwoon; Jeong, Soon Seog
- Biochemistry, Vol. 52, Issue 47
Individual Rate Constants for the Interaction of Ras Proteins with GTPase-Activating Proteins Determined by Fluorescence Spectroscopy
journal, April 1997
- Ahmadian, Mohammad Reza; Hoffmann, Ulrike; Goody, Roger S.
- Biochemistry, Vol. 36, Issue 15
Biochemical Characterization of a Novel KRAS Insertion Mutation from a Human Leukemia
journal, December 1996
- Bollag, Gideon; Adler, Felix; elMasry, Nadia
- Journal of Biological Chemistry, Vol. 271, Issue 51
Biochemical properties of Ha-ras encoded p21 mutants and mechanism of the autophosphorylation reaction.
journal, August 1988
- John, J.; Frech, M.; Wittinghofer, A.
- Journal of Biological Chemistry, Vol. 263, Issue 24
Evolution of AF6-RAS association and its implications in mixed-lineage leukemia
journal, October 2017
- Smith, Matthew J.; Ottoni, Elizabeth; Ishiyama, Noboru
- Nature Communications, Vol. 8, Issue 1
Integrated RAS signaling defined by parallel NMR detection of effectors and regulators
journal, January 2014
- Smith, Matthew J.; Ikura, Mitsuhiko
- Nature Chemical Biology, Vol. 10, Issue 3
Works referencing / citing this record:
Identification of microRNA-92a and the related combination biomarkers as promising substrates in predicting risk, recurrence and poor survival of colorectal cancer
journal, January 2019
- Peng, Qiliang; Shen, Yi; Lin, Kaisu
- Journal of Cancer, Vol. 10, Issue 14
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