11-13 May 2012 Helsingør - Denmark www.networkbio.org

ELENA NIKONOVA DIRK fEY† MIKhAIL TSYGANOV‡ BORIS KhOLODENKO
Temporal dynamics of two layer GTPase cascade with GDI binding
GTPases control intracellular signaling and are responsible for a variety of vital cellular mechanisms such
as cytoskeleton formation, motility and vesicle transport. Functioning of GTPases occurs due to monomeric
G proteins cycling between inactive GDP-bound and active GTP-bound states. The reaction is catalyzed
by guanine nucleotide exchange factors (GEFs) for the transformation from GDP to GTP and by GTPase
activating proteins (GAPs) for the reverse transformation. Malfunction of the GTPases often occurs due
to the deregulated expression and activities of GAP and GEF, which was found to be one of the causes of
tumorogenesis [2]. Guanine nucleotide dissociation inhibitors (GDIs) were also found to regulate the GTPase
cycles by binding to the inactive GDB-bound form and transporting the formed complex away from the membrane
to the cytosol. Previous characterization of spatiotemporal dynamics showed that models comprised
of two GTPases without GDI binding can exhibit 3 distinct regimes: sustained oscillations, bistable switches
and excitable behavior [1]. The current work explores the change in dynamics by allowing GDI to bind to
the active and inactive sites of both GTPases. In particular, our results show that as the dissociation and
association rates of GDI binding are varied, the two layer GTPase model can exhibit transformations within
previously outlined regimes.
References
[1] M.A.Tsyganov, W. Kolch and B.N. Kholodenko Molecular BioSystems, 2012.
[2] D. Vigil, J. Cherfils, K.L. Rossman and C.J. Der Nat. Rev. Cancer, 10(12), 842-857, 2010.
*Systems Biology Ireland, University College Dublin, Belfield, Dublin 4
†Systems Biology Ireland, University College Dublin, Belfield, Dublin 4
‡Institute of Theoretical and Experimental Biophysics, Pushchino, Moscow Region, Russia §Systems Biology
Ireland, University College Dublin, Belfield, Dublin 4
abStractS For PoSterS abStractS For PoSterS
ALExEY GOLTSOV (A), DANA fARATIAN(B), SIMON LANGDON(B), DAVID hARRISON(B), JAMES BOWN(A)
(A) CENTRE fOR RESEARCh IN INfORMATICS AND SYSTEMS PAThOLOGY, UNIVERSITY Of ABERTAY
DUNDEE, DUNDEE, UK (B) EDINBURGh BREAKThROUGh RESEARCh UNIT AND DIVISION Of PAThOLOGY,
WESTERN GENERAL hOSPITAL, UNIVERSITY Of EDINBURGh, EDINBURGh, UK
Systems biology of drug sensitivity-resistance transition in PI3K/AKT signalling in cancer
Systems biology offers a useful approach to study dependence of drug efficacy on oncogene-driven
transformations in drug target pathways relevant to cancer therapy. Systems approach was developed to
elucidate mechanisms underlying the changes of the efficacy of monoclonal antibody therapy (trastuzumab,
pertuzumab) targeting HER2 receptor at cancer genome transformation in the PI3K/AKT signalling network
(SN) [Goltsov et al Cell. Signalling 2011]. In silico experiments showed that HER2 inhibition sensitises the
SN both to external signals and to kinetic characteristics of the proteins and their expression levels. We suggested
that a drug-induced increase in SN sensitivity to internal perturbations, and specifically mutations,
causes SN fragility. In particular, the SN is vulnerable to mutations that compensate for drug action and this
may result in a drug sensitivity-to-resistance transition in SN [Goltsov et al Cell. Signalling 2012]. Modelling
showed the increase of SN sensitivity to typical aberrations in cancer causing drug resistance: loss of
PTEN activity, PI3K and AKT mutations, HER2 overexpression, and overproduction of GSK3ᴅ controlling
PTEN activity. In particular, the SN is vulnerable to mutations that compensate for drug action. PTEN loss or
PIK3CA mutation was shown to cause resistance to HER2 inhibition and leads to the restoration of maximal
pAKT signal with a consequent decrease in SN sensitivity. The drug-induced sensitivity of SN was tested in
experiments on ovarian cancer cells which demonstrated that HER2 inhibition increased SN sensitivity to
the second inhibitor targeting downstream pathway, in particular PI3K inhibition. The developed method is
proposed to be used in the pointed development of combined treatment of cancer which provides both synergetic
inhibition of SN activated in cancer and prevention of the SN from acquired drug resistance caused
by oncogenic mutations.
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