Substantial effort in recent years has been devoted to analyzing data based large-scale biological networks, which provide valuable insight into the topologies of complex biological networks but are rarely context specific and cannot be used to predict the responses of cell signaling proteins to specific ligands or compounds. In this work, we proposed a novel strategy to investigate kinase inhibitor induced pathway signatures by integrating multiplex data in Library of Integrated Network-based Cellular Signatures (LINCS), e.g. KINOMEscan data and cell proliferation/mitosis imaging data. Using this strategy, we first established a PC9 cell line specific pathway model to investigate the pathway signatures in PC9 cell line when perturbed by a small molecule kinase inhibitor GW843682. This specific pathway revealed the role of PI3K/AKT in modulating the cell proliferation process and the absence of two anti-proliferation links, which indicated a potential mechanism of abnormal expansion in PC9 cell number. Incorporating the pathway model for side effects on primary human hepatocytes, it was used to screen 27 kinase inhibitors in LINCS database and PF02341066, known as Crizotinib, was finally suggested with an optimal concentration 4.6 uM to suppress PC9 cancer cell expansion while avoiding severe damage to primary human hepatocytes. Drug combination analysis revealed that the synergistic effect region can be predicted straightforwardly based on a threshold which is an inherent property of each kinase inhibitor. Furthermore, this integration strategy can be easily extended to other specific cell lines to be a powerful tool for drug screen before clinical trials.
References
[1]
Alberts B, Wilson JH, Hunt T (2008) Molecular biology of the cell. New York: Garland Science. xxxiii, 1601, 1690 p.
[2]
Saez-Rodriguez J, Goldsipe A, Muhlich J, Alexopoulos LG, Millard B, et al. (2008) Flexible informatics for linking experimental data to mathematical models via DataRail. Bioinformatics 24: 840–847.
[3]
Hendriks BS, Espelin CW (2010) DataPflex: a MATLAB-based tool for the manipulation and visualization of multidimensional datasets. Bioinformatics 26: 432–433.
Geisler-Lee J, O’Toole N, Ammar R, Provart NJ, Millar AH, et al. (2007) A predicted interactome for Arabidopsis. Plant Physiol 145: 317–329.
[6]
Lee I, Date SV, Adai AT, Marcotte EM (2004) A probabilistic functional network of yeast genes. Science 306: 1555–1558.
[7]
Vazquez A, Flammini A, Maritan A, Vespignani A (2003) Global protein function prediction from protein-protein interaction networks. Nat Biotechnol 21: 697–700.
[8]
Heinrich R, Neel BG, Rapoport TA (2002) Mathematical models of protein kinase signal transduction. Mol Cell 9: 957–970.
[9]
Morris MK, Saez-Rodriguez J, Clarke DC, Sorger PK, Lauffenburger DA (2011) Training signaling pathway maps to biochemical data with constrained fuzzy logic: quantitative analysis of liver cell responses to inflammatory stimuli. PLoS Comput Biol 7: e1001099.
[10]
Zhang J, Yang PL, Gray NS (2009) Targeting cancer with small molecule kinase inhibitors. Nat Rev Cancer 9: 28–39.
[11]
Fabian MA, Biggs WH 3rd, Treiber DK, Atteridge CE, Azimioara MD, et al. (2005) A small molecule-kinase interaction map for clinical kinase inhibitors. Nat Biotechnol 23: 329–336.
[12]
Patricelli MP, Szardenings AK, Liyanage M, Nomanbhoy TK, Wu M, et al. (2007) Functional interrogation of the kinome using nucleotide acyl phosphates. Biochemistry 46: 350–358.
[13]
Kanehisa M, Goto S, Sato Y, Furumichi M, Tanabe M (2012) KEGG for integration and interpretation of large-scale molecular data sets. Nucleic Acids Res 40: D109–114.
[14]
Kanehisa M, Goto S (2000) KEGG: kyoto encyclopedia of genes and genomes. Nucleic Acids Res 28: 27–30.
[15]
Walter SA, Cutler RE Jr, Martinez R, Gishizky M, Hill RJ (2003) Stk10, a new member of the polo-like kinase kinase family highly expressed in hematopoietic tissue. J Biol Chem 278: 18221–18228.
[16]
Ellinger-Ziegelbauer H, Karasuyama H, Yamada E, Tsujikawa K, Todokoro K, et al. (2000) Ste20-like kinase (SLK), a regulatory kinase for polo-like kinase (Plk) during the G2/M transition in somatic cells. Genes Cells 5: 491–498.
[17]
Katayama K, Fujita N, Tsuruo T (2005) Akt/protein kinase B-dependent phosphorylation and inactivation of WEE1Hu promote cell cycle progression at G(2)/M transition. Molecular and Cellular Biology 25: 5725–5737.
[18]
Thornton TM, Rincon M (2009) Non-classical p38 map kinase functions: cell cycle checkpoints and survival. Int J Biol Sci 5: 44–51.
[19]
Xing J, Spitz MR, Lu C, Zhao H, Yang H, et al. (2007) Deficient G2-M and S checkpoints are associated with increased lung cancer risk: a case-control analysis. Cancer Epidemiol Biomarkers Prev 16: 1517–1522.
[20]
Kirouac DC, Madlambayan GJ, Yu M, Sykes EA, Ito C, et al. (2009) Cell-cell interaction networks regulate blood stem and progenitor cell fate. Mol Syst Biol 5: 293.
[21]
Gutenkunst RN, Waterfall JJ, Casey FP, Brown KS, Myers CR, et al. (2007) Universally sloppy parameter sensitivities in systems biology models. PLoS Comput Biol 3: 1871–1878.
[22]
Morohashi M, Winn AE, Borisuk MT, Bolouri H, Doyle J, et al. (2002) Robustness as a measure of plausibility in models of biochemical networks. Journal of Theoretical Biology 216: 19–30.
[23]
Fresno Vara JA, Casado E, de Castro J, Cejas P, Belda-Iniesta C, et al. (2004) PI3K/Akt signalling pathway and cancer. Cancer Treat Rev 30: 193–204.
[24]
Alvarez M, Roman E, Santos ES, Raez LE (2007) New targets for non-small-cell lung cancer therapy. Expert Rev Anticancer Ther 7: 1423–1437.
[25]
Mumoli N, Cei M, Cosimi A (2006) Drug-related hepatotoxicity. N Engl J Med 354: 2191–2193; author reply 2191–2193.
[26]
Grendell JH, McQuaid KR, Friedman SL (2003) Current diagnosis & treatment in gastroenterology. New York: Lang Medical Books/McGraw-Hill. xv, 867 p.
[27]
Ou SH, Bartlett CH, Mino-Kenudson M, Cui J, Iafrate AJ (2012) Crizotinib for the treatment of ALK-rearranged non-small cell lung cancer: a success story to usher in the second decade of molecular targeted therapy in oncology. Oncologist 17: 1351–1375.
[28]
BLISS CI (1939) The Toxicity of Poisons Applied Jointly. Annals of Applied Biology 26: 585–615.
[29]
Latt SA, Stetten G, Juergens LA, Willard HF, Scher CD (1975) Recent developments in the detection of deoxyribonucleic acid synthesis by 33258 Hoechst fluorescence. J Histochem Cytochem 23: 493–505.
[30]
Salic A, Mitchison TJ (2008) A chemical method for fast and sensitive detection of DNA synthesis in vivo. Proc Natl Acad Sci U S A 105: 2415–2420.
[31]
Jacobberger JW, Frisa PS, Sramkoski RM, Stefan T, Shults KE, et al. (2008) A new biomarker for mitotic cells. Cytometry A 73: 5–15.
[32]
Tsui M, Xie T, Orth JD, Carpenter AE, Rudnicki S, et al. (2009) An intermittent live cell imaging screen for siRNA enhancers and suppressors of a kinesin-5 inhibitor. PLoS One 4: e7339.
[33]
Srinivas M, Patnaik LM (1994) Adaptive Probabilities of Crossover and Mutation in Genetic Algorithms. Ieee Transactions on Systems Man and Cybernetics 24: 656–667.
