Loss of TRIM33 causes resistance to BET bromodomain inhibitors through MYC- and TGF-β-dependent mechanisms

Xiarong Shi; Valia T. Mihaylova; Leena Kuruvilla; Fang Chen; Stephen Viviano; Massimiliano Baldassarre; David Sperandio; Ruben Martinez; Peng Yue; Jamie G. Bates; David G. Breckenridge; Joseph Schlessinger; Benjamin E. Turk; David A. Calderwood

doi:10.1073/pnas.1608319113

Loss of TRIM33 causes resistance to BET bromodomain inhibitors through MYC- and TGF-β-dependent mechanisms

Xiarong Shi, Valia T. Mihaylova, Leena Kuruvilla, Fang Chen, Stephen Viviano, Massimiliano Baldassarre, David Sperandio, Ruben Martinez, Peng Yue, Jamie G. Bates, David G. Breckenridge, Joseph Schlessinger, Benjamin E. Turk, David A. Calderwood

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Abstract

Bromodomain and extraterminal domain protein inhibitors (BETi) hold great promise as a novel class of cancer therapeutics. Because acquired resistance typically limits durable responses to targeted therapies, it is important to understand mechanisms by which tumor cells adapt to BETi. Here, through pooled shRNA screening of colorectal cancer cells, we identified tripartite motif-containing protein 33 (TRIM33) as a factor promoting sensitivity to BETi. We demonstrate that loss of TRIM33 reprograms cancer cells to a more resistant state through at least two mechanisms. TRIM33 silencing attenuates down-regulation of MYC in response to BETi. Moreover, loss of TRIM33 enhances TGF-β receptor expression and signaling, and blocking TGF-β receptor activity potentiates the antiproliferative effect of BETi. These results describe a mechanism for BETi resistance and suggest that combining inhibition of TGF-β signaling with BET bromodomain inhibition may offer new therapeutic benefits.

Original language	English
Pages (from-to)	E4558-4566
Number of pages	9
Journal	PNAS
Volume	113
Issue number	31
Early online date	18 Jul 2016
DOIs	https://doi.org/10.1073/pnas.1608319113 https://doi.org/10.1073/pnas.1608319113/-/DCSupplemental
Publication status	Published - 2 Aug 2016

Keywords

bromodomain inhibitor
TRIM33
JQ1
drug resistance
TGF-β

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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http://www.pnas.org/site/misc/authorlicense.pdf The final published version of this manuscript is available at: http://www.pnas.org/content/113/31/E4558
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Shi, X., Mihaylova, V. T., Kuruvilla, L., Chen, F., Viviano, S., Baldassarre, M., Sperandio, D., Martinez, R., Yue, P., Bates, J. G., Breckenridge, D. G., Schlessinger, J., Turk, B. E., & Calderwood, D. A. (2016). Loss of TRIM33 causes resistance to BET bromodomain inhibitors through MYC- and TGF-β-dependent mechanisms. PNAS, 113(31), E4558-4566. https://doi.org/10.1073/pnas.1608319113, https://doi.org/10.1073/pnas.1608319113/-/DCSupplemental

Shi, X, Mihaylova, VT, Kuruvilla, L, Chen, F, Viviano, S, Baldassarre, M, Sperandio, D, Martinez, R, Yue, P, Bates, JG, Breckenridge, DG, Schlessinger, J, Turk, BE & Calderwood, DA 2016, 'Loss of TRIM33 causes resistance to BET bromodomain inhibitors through MYC- and TGF-β-dependent mechanisms', PNAS, vol. 113, no. 31, pp. E4558-4566. https://doi.org/10.1073/pnas.1608319113, https://doi.org/10.1073/pnas.1608319113/-/DCSupplemental

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title = "Loss of TRIM33 causes resistance to BET bromodomain inhibitors through MYC- and TGF-β-dependent mechanisms",

abstract = "Bromodomain and extraterminal domain protein inhibitors (BETi) hold great promise as a novel class of cancer therapeutics. Because acquired resistance typically limits durable responses to targeted therapies, it is important to understand mechanisms by which tumor cells adapt to BETi. Here, through pooled shRNA screening of colorectal cancer cells, we identified tripartite motif-containing protein 33 (TRIM33) as a factor promoting sensitivity to BETi. We demonstrate that loss of TRIM33 reprograms cancer cells to a more resistant state through at least two mechanisms. TRIM33 silencing attenuates down-regulation of MYC in response to BETi. Moreover, loss of TRIM33 enhances TGF-β receptor expression and signaling, and blocking TGF-β receptor activity potentiates the antiproliferative effect of BETi. These results describe a mechanism for BETi resistance and suggest that combining inhibition of TGF-β signaling with BET bromodomain inhibition may offer new therapeutic benefits.",

keywords = "bromodomain inhibitor, TRIM33, JQ1, drug resistance, TGF-β",

author = "Xiarong Shi and Mihaylova, {Valia T.} and Leena Kuruvilla and Fang Chen and Stephen Viviano and Massimiliano Baldassarre and David Sperandio and Ruben Martinez and Peng Yue and Bates, {Jamie G.} and Breckenridge, {David G.} and Joseph Schlessinger and Turk, {Benjamin E.} and Calderwood, {David A.}",

note = "ACKNOWLEDGMENTS. We thank Phillip B. Murray for help with the shRNA mapping pipeline and Francesc Lopez-Giraldez for help with RNAseq mapping software.",

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doi = "10.1073/pnas.1608319113",

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T1 - Loss of TRIM33 causes resistance to BET bromodomain inhibitors through MYC- and TGF-β-dependent mechanisms

AU - Shi, Xiarong

AU - Mihaylova, Valia T.

AU - Kuruvilla, Leena

AU - Chen, Fang

AU - Viviano, Stephen

AU - Baldassarre, Massimiliano

AU - Sperandio, David

AU - Martinez, Ruben

AU - Yue, Peng

AU - Bates, Jamie G.

AU - Breckenridge, David G.

AU - Schlessinger, Joseph

AU - Turk, Benjamin E.

AU - Calderwood, David A.

N1 - ACKNOWLEDGMENTS. We thank Phillip B. Murray for help with the shRNA mapping pipeline and Francesc Lopez-Giraldez for help with RNAseq mapping software.

PY - 2016/8/2

Y1 - 2016/8/2

N2 - Bromodomain and extraterminal domain protein inhibitors (BETi) hold great promise as a novel class of cancer therapeutics. Because acquired resistance typically limits durable responses to targeted therapies, it is important to understand mechanisms by which tumor cells adapt to BETi. Here, through pooled shRNA screening of colorectal cancer cells, we identified tripartite motif-containing protein 33 (TRIM33) as a factor promoting sensitivity to BETi. We demonstrate that loss of TRIM33 reprograms cancer cells to a more resistant state through at least two mechanisms. TRIM33 silencing attenuates down-regulation of MYC in response to BETi. Moreover, loss of TRIM33 enhances TGF-β receptor expression and signaling, and blocking TGF-β receptor activity potentiates the antiproliferative effect of BETi. These results describe a mechanism for BETi resistance and suggest that combining inhibition of TGF-β signaling with BET bromodomain inhibition may offer new therapeutic benefits.

AB - Bromodomain and extraterminal domain protein inhibitors (BETi) hold great promise as a novel class of cancer therapeutics. Because acquired resistance typically limits durable responses to targeted therapies, it is important to understand mechanisms by which tumor cells adapt to BETi. Here, through pooled shRNA screening of colorectal cancer cells, we identified tripartite motif-containing protein 33 (TRIM33) as a factor promoting sensitivity to BETi. We demonstrate that loss of TRIM33 reprograms cancer cells to a more resistant state through at least two mechanisms. TRIM33 silencing attenuates down-regulation of MYC in response to BETi. Moreover, loss of TRIM33 enhances TGF-β receptor expression and signaling, and blocking TGF-β receptor activity potentiates the antiproliferative effect of BETi. These results describe a mechanism for BETi resistance and suggest that combining inhibition of TGF-β signaling with BET bromodomain inhibition may offer new therapeutic benefits.

KW - bromodomain inhibitor

KW - TRIM33

KW - JQ1

KW - drug resistance

KW - TGF-β

U2 - 10.1073/pnas.1608319113

DO - 10.1073/pnas.1608319113

M3 - Article

C2 - 27432991

VL - 113

SP - E4558-4566

JO - PNAS

JF - PNAS

SN - 0027-8424

IS - 31

ER -

Loss of TRIM33 causes resistance to BET bromodomain inhibitors through MYC- and TGF-β-dependent mechanisms

Abstract

Keywords

UN SDGs

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