New insights into RAS biology reinvigorate interest in mathematical modeling of RAS signaling

Erickson, Keesha E.; Rukhlenko, Oleksii S.; Posner, Richard G.; Hlavacek, William S.; Kholodenko, Boris N.

doi:10.1016/j.semcancer.2018.02.008

Title: 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:

Erickson, Keesha E. ^[1]; Rukhlenko, Oleksii S. ^[2]; Posner, Richard G. ^[3]; Hlavacek, William S. ^[4]; Kholodenko, Boris N. ^[2]

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:: 2018-03-05

Research Org.:: Los Alamos National Lab. (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.

Copy to clipboard


                    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

Copy to clipboard


                    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.

Copy to clipboard


                    
@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         = {2018},

  month        = {3}

}

Copy to clipboard

Journal Article:

Free Publicly Available Full Text

Accepted Manuscript (DOE)

Publisher's Version of Record

https://doi.org/10.1016/j.semcancer.2018.02.008

Other availability

Search WorldCat to find libraries that may hold this journal

Citation Metrics:

Cited by: 3 works

Citation information provided by
Web of Science

Figures / Tables:

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 »

All figures and tables (7 total)

Save / Share:

Export Metadata

Save to My Library

Figures / Tables found in this record:

Figures/Tables have been extracted from DOE-funded journal article accepted manuscripts.

Similar Records in DOE PAGES and OSTI.GOV collections:

Molecular interaction between K-Ras and H-REV107 in the Ras signaling pathway

Journal Article Han, Chang Woo ; Jeong, Mi Suk ; Jang, Se Bok, E-mail: sbjang@pusan.ac.kr - Biochemical and Biophysical Research Communications

Ras proteins are small GTPases that serve as master moderators of a large number of signaling pathways involved in various cellular processes. Activating mutations in Ras are found in about one-third of cancers. H-REV107, a K-Ras binding protein, plays an important role in determining K-Ras function. H-REV107 is a member of the HREV107 family of class II tumor suppressor genes and a growth inhibitory Ras target gene that suppresses cellular growth, differentiation, and apoptosis. Expression of H-REV107 was strongly reduced in about 50% of human carcinoma cell lines. However, the specific molecular mechanism by which H-REV107 inhibits Ras is stillmore »« less
https://doi.org/10.1016/J.BBRC.2017.07.120
Analysis of Binding Site Hot Spots on the Surface of Ras GTPase

Journal Article Buhrman, Greg ; O, ; #8242 ; ... - J. Mol. Biol.

We have recently discovered an allosteric switch in Ras, bringing an additional level of complexity to this GTPase whose mutants are involved in nearly 30% of cancers. Upon activation of the allosteric switch, there is a shift in helix 3/loop 7 associated with a disorder to order transition in the active site. Here, we use a combination of multiple solvent crystal structures and computational solvent mapping (FTMap) to determine binding site hot spots in the 'off' and 'on' allosteric states of the GTP-bound form of H-Ras. Thirteen sites are revealed, expanding possible target sites for ligand binding well beyond themore »« less
https://doi.org/10.1016/j.jmb.2011.09.011
Ras-Related Small GTPases RalA and RalB Regulate Cellular Survival After Ionizing Radiation

Journal Article Kidd, Ambrose R ; Snider, Jared L ; Martin, Timothy D ; ... - International Journal of Radiation Oncology, Biology and Physics

Purpose: Oncogenic activation of Ras renders cancer cells resistant to ionizing radiation (IR), but the mechanisms have not been fully characterized. The Ras-like small GTPases RalA and RalB are downstream effectors of Ras function and are critical for both tumor growth and survival. The Ral effector RalBP1/RLIP76 mediates survival of mice after whole-body irradiation, but the role of the Ral GTPases themselves in response to IR is unknown. We have investigated the role of RalA and RalB in cellular responses to IR. Methods and Materials: RalA, RalB, and their major effectors RalBP1 and Sec5 were knocked down by stable expressionmore »« less
https://doi.org/10.1016/j.ijrobp.2010.03.023
Small molecule stabilization of the KSR inactive state antagonizes oncogenic Ras signalling

Journal Article Dhawan, Neil S. ; Scopton, Alex P. ; Dar, Arvin C. - Nature (London)

Deregulation of the Ras–mitogen activated protein kinase (MAPK) pathway is an early event in many different cancers and a key driver of resistance to targeted therapies. Sustained signalling through this pathway is caused most often by mutations in K-Ras, which biochemically favours the stabilization of active RAF signalling complexes. Kinase suppressor of Ras (KSR) is a MAPK scaffold that is subject to allosteric regulation through dimerization with RAF. Direct targeting of KSR could have important therapeutic implications for cancer; however, testing this hypothesis has been difficult owing to a lack of small-molecule antagonists of KSR function. Guided by KSR mutationsmore »« less
Cited by 35
https://doi.org/10.1038/nature19327

Full Text Available
The Plasma Membrane as a Competitive Inhibitor and Positive Allosteric Modulator of KRas4B Signaling

Journal Article Neale, Chris ; García, Angel E. - Biophysical Journal

Mutant Ras proteins are important drivers of human cancers, yet no approved drugs act directly on this difficult target. Over the last decade, the idea has emerged that oncogenic signaling can be diminished by molecules that drive Ras into orientations in which effector-binding interfaces are occluded by the cell membrane. To support this approach to drug discovery, we characterize the orientational preferences of membrane-bound K-Ras4B in 1.45-ms aggregate time of atomistic molecular dynamics simulations. Herein, individual simulations probe active or inactive states of Ras on membranes with or without anionic lipids. We find that the membrane orientation of Ras ismore »« less
Cited by 5
https://doi.org/10.1016/j.bpj.2019.12.039

Similar Records