Resistance to BET Bromodomain Inhibitors Is Mediated by Kinome Reprogramming in Ovarian Cancer

Alison M. Kurimchak; Claude Shelton; Kelly E. Duncan; Katherine J. Johnson; Jennifer Brown; Shane O'Brien; Rashid Gabbasov; Lauren S. Fink; Yuesheng Li; Nicole Lounsbury; Magid Abou-Gharbia; Wayne E. Childers; Denise C. Connolly; Jonathan Chernoff; Jeffrey R. Peterson; James S. Duncan

doi:10.1016/j.celrep.2016.06.091

Resistance to BET Bromodomain Inhibitors Is Mediated by Kinome Reprogramming in Ovarian Cancer

Alison M. Kurimchak, Claude Shelton, Kelly E. Duncan, Katherine J. Johnson, Jennifer Brown, Shane O'Brien, Rashid Gabbasov, Lauren S. Fink, Yuesheng Li, Nicole Lounsbury, Magid Abou-Gharbia, Wayne E. Childers, Denise C. Connolly, Jonathan Chernoff, Jeffrey R. Peterson, James S. Duncan

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Abstract

Small-molecule BET bromodomain inhibitors (BETis) are actively being pursued in clinical trials for the treatment of a variety of cancers, but the mechanisms of resistance to BETis remain poorly understood. Using a mass spectrometry approach that globally measures kinase signaling at the proteomic level, we evaluated the response of the kinome to targeted BETi treatment in a panel of BRD4-dependent ovarian carcinoma (OC) cell lines. Despite initial inhibitory effects of BETi, OC cells acquired resistance following sustained treatment with the BETi JQ1. Through application of multiplexed inhibitor beads (MIBs) and mass spectrometry, we demonstrate that BETi resistance is mediated by adaptive kinome reprogramming, where activation of compensatory pro-survival kinase networks overcomes BET protein inhibition. Furthermore, drug combinations blocking these kinases may prevent or delay the development of drug resistance and enhance the efficacy of BETi therapy.

Original language	English
Pages (from-to)	1273-1286
Number of pages	14
Journal	Cell Reports
Volume	16
Issue number	5
DOIs	https://doi.org/10.1016/j.celrep.2016.06.091
State	Published - Aug 2 2016

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Kurimchak, A. M., Shelton, C., Duncan, K. E., Johnson, K. J., Brown, J., O'Brien, S., Gabbasov, R., Fink, L. S., Li, Y., Lounsbury, N., Abou-Gharbia, M., Childers, W. E., Connolly, D. C., Chernoff, J., Peterson, J. R., & Duncan, J. S. (2016). Resistance to BET Bromodomain Inhibitors Is Mediated by Kinome Reprogramming in Ovarian Cancer. Cell Reports, 16(5), 1273-1286. https://doi.org/10.1016/j.celrep.2016.06.091

@article{2948f53bbe61478d9c1143ab8c074d96,

title = "Resistance to BET Bromodomain Inhibitors Is Mediated by Kinome Reprogramming in Ovarian Cancer",

abstract = "Small-molecule BET bromodomain inhibitors (BETis) are actively being pursued in clinical trials for the treatment of a variety of cancers, but the mechanisms of resistance to BETis remain poorly understood. Using a mass spectrometry approach that globally measures kinase signaling at the proteomic level, we evaluated the response of the kinome to targeted BETi treatment in a panel of BRD4-dependent ovarian carcinoma (OC) cell lines. Despite initial inhibitory effects of BETi, OC cells acquired resistance following sustained treatment with the BETi JQ1. Through application of multiplexed inhibitor beads (MIBs) and mass spectrometry, we demonstrate that BETi resistance is mediated by adaptive kinome reprogramming, where activation of compensatory pro-survival kinase networks overcomes BET protein inhibition. Furthermore, drug combinations blocking these kinases may prevent or delay the development of drug resistance and enhance the efficacy of BETi therapy.",

author = "Kurimchak, {Alison M.} and Claude Shelton and Duncan, {Kelly E.} and Johnson, {Katherine J.} and Jennifer Brown and Shane O'Brien and Rashid Gabbasov and Fink, {Lauren S.} and Yuesheng Li and Nicole Lounsbury and Magid Abou-Gharbia and Childers, {Wayne E.} and Connolly, {Denise C.} and Jonathan Chernoff and Peterson, {Jeffrey R.} and Duncan, {James S.}",

note = "Publisher Copyright: {\textcopyright} 2016 The Author(s)",

year = "2016",

month = aug,

day = "2",

doi = "10.1016/j.celrep.2016.06.091",

language = "English",

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Kurimchak, AM, Shelton, C, Duncan, KE, Johnson, KJ, Brown, J, O'Brien, S, Gabbasov, R, Fink, LS, Li, Y, Lounsbury, N, Abou-Gharbia, M, Childers, WE, Connolly, DC , Chernoff, J, Peterson, JR & Duncan, JS 2016, 'Resistance to BET Bromodomain Inhibitors Is Mediated by Kinome Reprogramming in Ovarian Cancer', Cell Reports, vol. 16, no. 5, pp. 1273-1286. https://doi.org/10.1016/j.celrep.2016.06.091

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T1 - Resistance to BET Bromodomain Inhibitors Is Mediated by Kinome Reprogramming in Ovarian Cancer

AU - Kurimchak, Alison M.

AU - Shelton, Claude

AU - Duncan, Kelly E.

AU - Johnson, Katherine J.

AU - Brown, Jennifer

AU - O'Brien, Shane

AU - Gabbasov, Rashid

AU - Fink, Lauren S.

AU - Li, Yuesheng

AU - Lounsbury, Nicole

AU - Abou-Gharbia, Magid

AU - Childers, Wayne E.

AU - Connolly, Denise C.

AU - Chernoff, Jonathan

AU - Peterson, Jeffrey R.

AU - Duncan, James S.

PY - 2016/8/2

Y1 - 2016/8/2

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AB - Small-molecule BET bromodomain inhibitors (BETis) are actively being pursued in clinical trials for the treatment of a variety of cancers, but the mechanisms of resistance to BETis remain poorly understood. Using a mass spectrometry approach that globally measures kinase signaling at the proteomic level, we evaluated the response of the kinome to targeted BETi treatment in a panel of BRD4-dependent ovarian carcinoma (OC) cell lines. Despite initial inhibitory effects of BETi, OC cells acquired resistance following sustained treatment with the BETi JQ1. Through application of multiplexed inhibitor beads (MIBs) and mass spectrometry, we demonstrate that BETi resistance is mediated by adaptive kinome reprogramming, where activation of compensatory pro-survival kinase networks overcomes BET protein inhibition. Furthermore, drug combinations blocking these kinases may prevent or delay the development of drug resistance and enhance the efficacy of BETi therapy.

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DO - 10.1016/j.celrep.2016.06.091

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EP - 1286

JO - Cell Reports

JF - Cell Reports

IS - 5

ER -

Resistance to BET Bromodomain Inhibitors Is Mediated by Kinome Reprogramming in Ovarian Cancer

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