{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T03:42:59Z","timestamp":1781149379956,"version":"3.54.1"},"reference-count":28,"publisher":"Springer Science and Business Media LLC","issue":"1","content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Syst Biol"],"published-print":{"date-parts":[[2011,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:sec>\n            <jats:title>Background<\/jats:title>\n            <jats:p>It has been shown in experimental and theoretical work that covalently modified signaling cascades naturally exhibit bidirectional signal propagation via a phenomenon known as retroactivity. An important consequence of retroactivity, which arises due to enzyme sequestration in covalently modified signaling cascades, is that a downstream perturbation can produce a response in a component upstream of the perturbation without the need for explicit feedback connections. Retroactivity may, therefore, play an important role in the cellular response to a targeted therapy. Kinase inhibitors are a class of targeted therapies designed to interfere with a specific kinase molecule in a dysregulated signaling pathway. While extremely promising as anti-cancer agents, kinase inhibitors may produce undesirable off-target effects by non-specific interactions or pathway cross-talk. We hypothesize that targeted therapies such as kinase inhibitors can produce off-target effects as a consequence of retroactivity alone.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>We used a computational model and a series of simple signaling motifs to test the hypothesis. Our results indicate that within physiologically and therapeutically relevant ranges for all parameters, a targeted inhibitor can naturally induce an off-target effect via retroactivity. The kinetics governing covalent modification cycles in a signaling network were more important for propagating an upstream off-target effect in our models than the kinetics governing the targeted therapy itself. Our results also reveal the surprising and crucial result that kinase inhibitors have the capacity to turn \"on\" an otherwise \"off\" parallel cascade when two cascades share an upstream activator.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>A proper and detailed characterization of a pathway's structure is important for identifying the optimal protein to target as well as what concentration of the targeted therapy is required to modulate the pathway in a safe and effective manner. We believe our results support the position that such characterizations should consider retroactivity as a robust potential source of off-target effects induced by kinase inhibitors and other targeted therapies.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/1752-0509-5-156","type":"journal-article","created":{"date-parts":[[2011,10,5]],"date-time":"2011-10-05T00:32:50Z","timestamp":1317774770000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":41,"title":["Kinase inhibitors can produce off-target effects and activate linked pathways by retroactivity"],"prefix":"10.1186","volume":"5","author":[{"given":"Michelle L","family":"Wynn","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alejandra C","family":"Ventura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacques A","family":"Sepulchre","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H\u00e9ctor J","family":"Garc\u00eda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sofia D","family":"Merajver","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2011,10,4]]},"reference":[{"key":"826_CR1","doi-asserted-by":"publisher","first-page":"165","DOI":"10.1038\/nrm1838","volume":"7","author":"BN Kholodenko","year":"2006","unstructured":"Kholodenko BN: Cell-signalling dynamics in time and space. Nat Rev Mol Cell Biol. 2006, 7: 165-176. 10.1038\/nrm1838.","journal-title":"Nat Rev Mol Cell Biol"},{"key":"826_CR2","doi-asserted-by":"publisher","first-page":"294","DOI":"10.1038\/nature03095","volume":"432","author":"C Sawyers","year":"2004","unstructured":"Sawyers C: Targeted cancer therapy. Nature. 2004, 432: 294-297. 10.1038\/nature03095.","journal-title":"Nature"},{"key":"826_CR3","doi-asserted-by":"publisher","first-page":"1668","DOI":"10.1124\/mol.107.043794","volume":"73","author":"N Kumar","year":"2008","unstructured":"Kumar N, Afeyan R, Kim HD, Lauffenburger DA: Multipathway model enables prediction of kinase inhibitor cross-talk effects on migration of Her2-overexpressing mammary epithelial cells. Mol Pharmacol. 2008, 73: 1668-1678. 10.1124\/mol.107.043794.","journal-title":"Mol Pharmacol"},{"key":"826_CR4","doi-asserted-by":"publisher","first-page":"e1000041","DOI":"10.1371\/journal.pcbi.1000041","volume":"4","author":"AC Ventura","year":"2008","unstructured":"Ventura AC, Sepulchre JA, Merajver SD: A hidden feedback in signaling cascades is revealed. PLoS Comput Biol. 2008, 4: e1000041-10.1371\/journal.pcbi.1000041.","journal-title":"PLoS Comput Biol"},{"key":"826_CR5","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1038\/msb4100204","volume":"4","author":"D Del Vecchio","year":"2008","unstructured":"Del Vecchio D, Ninfa AJ, Sontag ED: Modular cell biology: retroactivity and insulation. Mol Syst Biol. 2008, 4: 161-","journal-title":"Mol Syst Biol"},{"key":"826_CR6","doi-asserted-by":"publisher","first-page":"400","DOI":"10.1158\/0008-5472.CAN-08-4422","volume":"69","author":"AC Ventura","year":"2009","unstructured":"Ventura AC, Jackson TL, Merajver SD: On the role of cell signaling models in cancer research. Cancer Res. 2009, 69: 400-402. 10.1158\/0008-5472.CAN-08-4422.","journal-title":"Cancer Res"},{"key":"826_CR7","doi-asserted-by":"publisher","first-page":"10032","DOI":"10.1073\/pnas.0913815107","volume":"107","author":"AC Ventura","year":"2010","unstructured":"Ventura AC, Jiang P, Van Wassenhove L, Del Vecchio D, Merajver SD, Ninfa AJ: Signaling properties of a covalent modification cycle are altered by a downstream target. Proc Natl Acad Sci USA. 2010, 107: 10032-10037. 10.1073\/pnas.0913815107.","journal-title":"Proc Natl Acad Sci USA"},{"key":"826_CR8","doi-asserted-by":"publisher","first-page":"467","DOI":"10.1038\/msb.2010.121","volume":"7","author":"Y Kim","year":"2011","unstructured":"Kim Y, Paroush Z, Nairz K, Hafen E, Jimenez G, Shvartsman SY: Substrate-dependent control of MAPK phosphorylation in vivo. Mol Syst Biol. 2011, 7: 467-","journal-title":"Mol Syst Biol"},{"key":"826_CR9","doi-asserted-by":"publisher","first-page":"1617","DOI":"10.1016\/j.bpj.2011.02.014","volume":"100","author":"HR Ossareh","year":"2011","unstructured":"Ossareh HR, Ventura AC, Merajver SD, Del Vecchio D: Long signaling cascades tend to attenuate retroactivity. Biophys J. 2011, 100: 1617-1626. 10.1016\/j.bpj.2011.02.014.","journal-title":"Biophys J"},{"key":"826_CR10","doi-asserted-by":"publisher","first-page":"2005 0023","DOI":"10.1038\/msb4100031","volume":"1","author":"NL Komarova","year":"2005","unstructured":"Komarova NL, Zou X, Nie Q, Bardwell L: A theoretical framework for specificity in cell signaling. Mol Syst Biol. 2005, 1: 2005 0023-","journal-title":"Mol Syst Biol"},{"key":"826_CR11","doi-asserted-by":"publisher","first-page":"537","DOI":"10.1038\/nrc2694","volume":"9","author":"EF Wagner","year":"2009","unstructured":"Wagner EF, Nebreda AR: Signal integration by JNK and p38 MAPK pathways in cancer development. Nat Rev Cancer. 2009, 9: 537-549. 10.1038\/nrc2694.","journal-title":"Nat Rev Cancer"},{"key":"826_CR12","volume-title":"Fundamentals of enzyme kinetics","author":"A Cornish-Bowden","year":"2004","unstructured":"Cornish-Bowden A: Fundamentals of enzyme kinetics. 2004, London: Portland Press, 3","edition":"3"},{"key":"826_CR13","doi-asserted-by":"publisher","first-page":"6840","DOI":"10.1073\/pnas.78.11.6840","volume":"78","author":"A Goldbeter","year":"1981","unstructured":"Goldbeter A, Koshland DE: An amplified sensitivity arising from covalent modification in biological systems. Proc Natl Acad Sci USA. 1981, 78: 6840-6844. 10.1073\/pnas.78.11.6840.","journal-title":"Proc Natl Acad Sci USA"},{"key":"826_CR14","doi-asserted-by":"publisher","first-page":"178","DOI":"10.1016\/j.jtbi.2008.04.011","volume":"254","author":"S Marino","year":"2008","unstructured":"Marino S, Hogue IB, Ray CJ, Kirschner DE: A methodology for performing global uncertainty and sensitivity analysis in systems biology. J Theor Biol. 2008, 254: 178-196. 10.1016\/j.jtbi.2008.04.011.","journal-title":"J Theor Biol"},{"key":"826_CR15","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1080\/00401706.2000.10485979","volume":"42","author":"MD McKay","year":"2000","unstructured":"McKay MD, Beckman RJ, Conover WJ: A Comparison of Three Methods for selecting Values of Input Variables in the Analysis of Output from a Computer Code. Technometrics. 2000, 42: 55-61. 10.2307\/1271432.","journal-title":"Technometrics"},{"key":"826_CR16","doi-asserted-by":"publisher","first-page":"126","DOI":"10.1126\/science.1156951","volume":"321","author":"TY Tsai","year":"2008","unstructured":"Tsai TY, Choi YS, Ma W, Pomerening JR, Tang C, Ferrell JE: Robust, tunable biological oscillations from interlinked positive and negative feedback loops. Science. 2008, 321: 126-129. 10.1126\/science.1156951.","journal-title":"Science"},{"key":"826_CR17","volume-title":"Parametric sensitivity in chemical systems","author":"A Varma","year":"2005","unstructured":"Varma A, Morbidelli M, Wu H: Parametric sensitivity in chemical systems. 2005, Cambridge ; New York: Cambridge University Press"},{"key":"826_CR18","doi-asserted-by":"publisher","first-page":"10078","DOI":"10.1073\/pnas.93.19.10078","volume":"93","author":"CY Huang","year":"1996","unstructured":"Huang CY, Ferrell JE: Ultrasensitivity in the mitogen-activated protein kinase cascade. Proc Natl Acad Sci USA. 1996, 93: 10078-10083. 10.1073\/pnas.93.19.10078.","journal-title":"Proc Natl Acad Sci USA"},{"key":"826_CR19","doi-asserted-by":"publisher","first-page":"220","DOI":"10.1126\/science.7089556","volume":"217","author":"DE Koshland","year":"1982","unstructured":"Koshland DE, Goldbeter A, Stock JB: Amplification and adaptation in regulatory and sensory systems. Science. 1982, 217: 220-225. 10.1126\/science.7089556.","journal-title":"Science"},{"key":"826_CR20","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1038\/ng1293","volume":"36","author":"G Lahav","year":"2004","unstructured":"Lahav G, Rosenfeld N, Sigal A, Geva-Zatorsky N, Levine AJ, Elowitz MB, Alon U: Dynamics of the p53-Mdm2 feedback loop in individual cells. Nat Genet. 2004, 36: 147-150. 10.1038\/ng1293.","journal-title":"Nat Genet"},{"key":"826_CR21","doi-asserted-by":"publisher","first-page":"488","DOI":"10.4161\/cc.4.3.1548","volume":"4","author":"A Ciliberto","year":"2005","unstructured":"Ciliberto A, Novak B, Tyson JJ: Steady states and oscillations in the p53\/Mdm2 network. Cell Cycle. 2005, 4: 488-493. 10.4161\/cc.4.3.1548.","journal-title":"Cell Cycle"},{"key":"826_CR22","doi-asserted-by":"publisher","first-page":"7391","DOI":"10.1073\/pnas.0609757104","volume":"104","author":"K Siddiquee","year":"2007","unstructured":"Siddiquee K, Zhang S, Guida WC, Blaskovich MA, Greedy B, Lawrence HR, Yip ML, Jove R, McLaughlin MM, Lawrence NJ, et al, et al.: Selective chemical probe inhibitor of Stat3, identified through structure-based virtual screening, induces antitumor activity. Proc Natl Acad Sci USA. 2007, 104: 7391-7396. 10.1073\/pnas.0609757104.","journal-title":"Proc Natl Acad Sci USA"},{"key":"826_CR23","doi-asserted-by":"publisher","first-page":"1281","DOI":"10.1242\/jcs.00963","volume":"117","author":"JS Rawlings","year":"2004","unstructured":"Rawlings JS, Rosler KM, Harrison DA: The JAK\/STAT signaling pathway. J Cell Sci. 2004, 117: 1281-1283. 10.1242\/jcs.00963.","journal-title":"J Cell Sci"},{"key":"826_CR24","doi-asserted-by":"publisher","first-page":"2366","DOI":"10.1158\/0008-5472.CAN-07-5783","volume":"68","author":"N Rhodes","year":"2008","unstructured":"Rhodes N, Heerding DA, Duckett DR, Eberwein DJ, Knick VB, Lansing TJ, McConnell RT, Gilmer TM, Zhang SY, Robell K, et al, et al.: Characterization of an Akt kinase inhibitor with potent pharmacodynamic and antitumor activity. Cancer Res. 2008, 68: 2366-2374. 10.1158\/0008-5472.CAN-07-5783.","journal-title":"Cancer Res"},{"key":"826_CR25","doi-asserted-by":"publisher","first-page":"ra67","DOI":"10.1126\/scisignal.2001083","volume":"3","author":"I Astsaturov","year":"2010","unstructured":"Astsaturov I, Ratushny V, Sukhanova A, Einarson MB, Bagnyukova T, Zhou Y, Devarajan K, Silverman JS, Tikhmyanova N, Skobeleva N, et al, et al.: Synthetic lethal screen of an EGFR-centered network to improve targeted therapies. Sci Signal. 2010, 3: ra67-10.1126\/scisignal.2001083.","journal-title":"Sci Signal"},{"key":"826_CR26","doi-asserted-by":"publisher","first-page":"831","DOI":"10.1016\/S0092-8674(03)00190-9","volume":"112","author":"M Azam","year":"2003","unstructured":"Azam M, Latek RR, Daley GQ: Mechanisms of autoinhibition and STI-571\/imatinib resistance revealed by mutagenesis of BCR-ABL. Cell. 2003, 112: 831-843. 10.1016\/S0092-8674(03)00190-9.","journal-title":"Cell"},{"key":"826_CR27","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1186\/1752-0509-4-92","volume":"4","author":"C Li","year":"2010","unstructured":"Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, et al, et al.: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol. 2010, 4: 92-10.1186\/1752-0509-4-92.","journal-title":"BMC Syst Biol"},{"key":"826_CR28","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1016\/S0022-5193(03)00247-9","volume":"225","author":"N Bluthgen","year":"2003","unstructured":"Bluthgen N, Herzel H: How robust are switches in intracellular signaling cascades?. J Theor Biol. 2003, 225: 293-300. 10.1016\/S0022-5193(03)00247-9.","journal-title":"J Theor Biol"}],"container-title":["BMC Systems Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/1752-0509-5-156.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,9,1]],"date-time":"2021-09-01T17:56:26Z","timestamp":1630518986000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmcsystbiol.biomedcentral.com\/articles\/10.1186\/1752-0509-5-156"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2011,10,4]]},"references-count":28,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2011,12]]}},"alternative-id":["826"],"URL":"https:\/\/doi.org\/10.1186\/1752-0509-5-156","relation":{},"ISSN":["1752-0509"],"issn-type":[{"value":"1752-0509","type":"electronic"}],"subject":[],"published":{"date-parts":[[2011,10,4]]},"assertion":[{"value":"24 June 2011","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 October 2011","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 October 2011","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}}],"article-number":"156"}}