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The Novel Bromodomain and Extraterminal Domain Inhibitor INCB054329 Induces Vulnerabilities in Myeloma Cells That Inform Rational Combination Strategies
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| Zeitschriftentitel: | Clinical Cancer Research |
|---|---|
| Personen und Körperschaften: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
| In: | Clinical Cancer Research, 25, 2019, 1, S. 300-311 |
| Format: | E-Article |
| Sprache: | Englisch |
| veröffentlicht: |
American Association for Cancer Research (AACR)
|
| Schlagwörter: |
| author_facet |
Stubbs, Matthew C. Burn, Timothy C. Sparks, Richard Maduskuie, Thomas Diamond, Sharon Rupar, Mark Wen, Xiaoming Volgina, Alla Zolotarjova, Nina Waeltz, Paul Favata, Margaret Jalluri, Ravi Liu, Huiqing Liu, Xuesong Mike Li, Jun Collins, Robert Falahatpisheh, Nikoo Polam, Padmaja DiMatteo, Darlise Feldman, Patricia Dostalik, Valerie Thekkat, Pramod Gardiner, Christine He, Xin Li, Yanlong Covington, Maryanne Wynn, Richard Ruggeri, Bruce Yeleswaram, Swamy Xue, Chu-Biao Yao, Wenqing Combs, Andrew P. Huber, Reid Hollis, Gregory Scherle, Peggy Liu, Phillip C.C. Stubbs, Matthew C. Burn, Timothy C. Sparks, Richard Maduskuie, Thomas Diamond, Sharon Rupar, Mark Wen, Xiaoming Volgina, Alla Zolotarjova, Nina Waeltz, Paul Favata, Margaret Jalluri, Ravi Liu, Huiqing Liu, Xuesong Mike Li, Jun Collins, Robert Falahatpisheh, Nikoo Polam, Padmaja DiMatteo, Darlise Feldman, Patricia Dostalik, Valerie Thekkat, Pramod Gardiner, Christine He, Xin Li, Yanlong Covington, Maryanne Wynn, Richard Ruggeri, Bruce Yeleswaram, Swamy Xue, Chu-Biao Yao, Wenqing Combs, Andrew P. Huber, Reid Hollis, Gregory Scherle, Peggy Liu, Phillip C.C. |
|---|---|
| author |
Stubbs, Matthew C. Burn, Timothy C. Sparks, Richard Maduskuie, Thomas Diamond, Sharon Rupar, Mark Wen, Xiaoming Volgina, Alla Zolotarjova, Nina Waeltz, Paul Favata, Margaret Jalluri, Ravi Liu, Huiqing Liu, Xuesong Mike Li, Jun Collins, Robert Falahatpisheh, Nikoo Polam, Padmaja DiMatteo, Darlise Feldman, Patricia Dostalik, Valerie Thekkat, Pramod Gardiner, Christine He, Xin Li, Yanlong Covington, Maryanne Wynn, Richard Ruggeri, Bruce Yeleswaram, Swamy Xue, Chu-Biao Yao, Wenqing Combs, Andrew P. Huber, Reid Hollis, Gregory Scherle, Peggy Liu, Phillip C.C. |
| spellingShingle |
Stubbs, Matthew C. Burn, Timothy C. Sparks, Richard Maduskuie, Thomas Diamond, Sharon Rupar, Mark Wen, Xiaoming Volgina, Alla Zolotarjova, Nina Waeltz, Paul Favata, Margaret Jalluri, Ravi Liu, Huiqing Liu, Xuesong Mike Li, Jun Collins, Robert Falahatpisheh, Nikoo Polam, Padmaja DiMatteo, Darlise Feldman, Patricia Dostalik, Valerie Thekkat, Pramod Gardiner, Christine He, Xin Li, Yanlong Covington, Maryanne Wynn, Richard Ruggeri, Bruce Yeleswaram, Swamy Xue, Chu-Biao Yao, Wenqing Combs, Andrew P. Huber, Reid Hollis, Gregory Scherle, Peggy Liu, Phillip C.C. Clinical Cancer Research The Novel Bromodomain and Extraterminal Domain Inhibitor INCB054329 Induces Vulnerabilities in Myeloma Cells That Inform Rational Combination Strategies Cancer Research Oncology |
| author_sort |
stubbs, matthew c. |
| spelling |
Stubbs, Matthew C. Burn, Timothy C. Sparks, Richard Maduskuie, Thomas Diamond, Sharon Rupar, Mark Wen, Xiaoming Volgina, Alla Zolotarjova, Nina Waeltz, Paul Favata, Margaret Jalluri, Ravi Liu, Huiqing Liu, Xuesong Mike Li, Jun Collins, Robert Falahatpisheh, Nikoo Polam, Padmaja DiMatteo, Darlise Feldman, Patricia Dostalik, Valerie Thekkat, Pramod Gardiner, Christine He, Xin Li, Yanlong Covington, Maryanne Wynn, Richard Ruggeri, Bruce Yeleswaram, Swamy Xue, Chu-Biao Yao, Wenqing Combs, Andrew P. Huber, Reid Hollis, Gregory Scherle, Peggy Liu, Phillip C.C. 1078-0432 1557-3265 American Association for Cancer Research (AACR) Cancer Research Oncology http://dx.doi.org/10.1158/1078-0432.ccr-18-0098 <jats:title>Abstract</jats:title> <jats:sec> <jats:title>Purpose:</jats:title> <jats:p>Bromodomain and extraterminal domain (BET) proteins regulate the expression of many cancer-associated genes and pathways; BET inhibitors have demonstrated activity in diverse models of hematologic and solid tumors. We report the preclinical characterization of INCB054329, a structurally distinct BET inhibitor that has been investigated in phase I clinical trials.</jats:p> </jats:sec> <jats:sec> <jats:title>Experimental Design:</jats:title> <jats:p>We used multiple myeloma models to investigate vulnerabilities created by INCB054329 treatment that could inform rational combinations.</jats:p> </jats:sec> <jats:sec> <jats:title>Results:</jats:title> <jats:p>In addition to c-MYC, INCB054329 decreased expression of oncogenes FGFR3 and NSD2/MMSET/WHSC1, which are deregulated in t(4;14)-rearranged cell lines. The profound suppression of FGFR3 sensitized the t(4;14)-positive cell line OPM-2 to combined treatment with a fibroblast growth factor receptor inhibitor in vivo. In addition, we show that BET inhibition across multiple myeloma cell lines resulted in suppressed interleukin (IL)-6 Janus kinase–signal transducers and activators of transcription (JAK–STAT) signaling. INCB054329 displaced binding of BRD4 to the promoter of IL6 receptor (IL6R) leading to reduced levels of IL6R and diminished signaling through STAT3. Combination with JAK inhibitors (ruxolitinib or itacitinib) further reduced JAK–STAT signaling and synergized to inhibit myeloma cell growth in vitro and in vivo. This combination potentiated tumor growth inhibition in vivo, even in the MM1.S model of myeloma that is not intrinsically sensitive to JAK inhibition alone.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions:</jats:title> <jats:p>Preclinical data reveal insights into vulnerabilities created in myeloma cells by BET protein inhibition and potential strategies that can be leveraged in clinical studies to enhance the activity of INCB054329.</jats:p> </jats:sec> The Novel Bromodomain and Extraterminal Domain Inhibitor INCB054329 Induces Vulnerabilities in Myeloma Cells That Inform Rational Combination Strategies Clinical Cancer Research |
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10.1158/1078-0432.ccr-18-0098 |
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American Association for Cancer Research (AACR), 2019 |
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American Association for Cancer Research (AACR), 2019 |
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1078-0432 1557-3265 |
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Clinical Cancer Research |
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| title |
The Novel Bromodomain and Extraterminal Domain Inhibitor INCB054329 Induces Vulnerabilities in Myeloma Cells That Inform Rational Combination Strategies |
| title_unstemmed |
The Novel Bromodomain and Extraterminal Domain Inhibitor INCB054329 Induces Vulnerabilities in Myeloma Cells That Inform Rational Combination Strategies |
| title_full |
The Novel Bromodomain and Extraterminal Domain Inhibitor INCB054329 Induces Vulnerabilities in Myeloma Cells That Inform Rational Combination Strategies |
| title_fullStr |
The Novel Bromodomain and Extraterminal Domain Inhibitor INCB054329 Induces Vulnerabilities in Myeloma Cells That Inform Rational Combination Strategies |
| title_full_unstemmed |
The Novel Bromodomain and Extraterminal Domain Inhibitor INCB054329 Induces Vulnerabilities in Myeloma Cells That Inform Rational Combination Strategies |
| title_short |
The Novel Bromodomain and Extraterminal Domain Inhibitor INCB054329 Induces Vulnerabilities in Myeloma Cells That Inform Rational Combination Strategies |
| title_sort |
the novel bromodomain and extraterminal domain inhibitor incb054329 induces vulnerabilities in myeloma cells that inform rational combination strategies |
| topic |
Cancer Research Oncology |
| url |
http://dx.doi.org/10.1158/1078-0432.ccr-18-0098 |
| publishDate |
2019 |
| physical |
300-311 |
| description |
<jats:title>Abstract</jats:title>
<jats:sec>
<jats:title>Purpose:</jats:title>
<jats:p>Bromodomain and extraterminal domain (BET) proteins regulate the expression of many cancer-associated genes and pathways; BET inhibitors have demonstrated activity in diverse models of hematologic and solid tumors. We report the preclinical characterization of INCB054329, a structurally distinct BET inhibitor that has been investigated in phase I clinical trials.</jats:p>
</jats:sec>
<jats:sec>
<jats:title>Experimental Design:</jats:title>
<jats:p>We used multiple myeloma models to investigate vulnerabilities created by INCB054329 treatment that could inform rational combinations.</jats:p>
</jats:sec>
<jats:sec>
<jats:title>Results:</jats:title>
<jats:p>In addition to c-MYC, INCB054329 decreased expression of oncogenes FGFR3 and NSD2/MMSET/WHSC1, which are deregulated in t(4;14)-rearranged cell lines. The profound suppression of FGFR3 sensitized the t(4;14)-positive cell line OPM-2 to combined treatment with a fibroblast growth factor receptor inhibitor in vivo. In addition, we show that BET inhibition across multiple myeloma cell lines resulted in suppressed interleukin (IL)-6 Janus kinase–signal transducers and activators of transcription (JAK–STAT) signaling. INCB054329 displaced binding of BRD4 to the promoter of IL6 receptor (IL6R) leading to reduced levels of IL6R and diminished signaling through STAT3. Combination with JAK inhibitors (ruxolitinib or itacitinib) further reduced JAK–STAT signaling and synergized to inhibit myeloma cell growth in vitro and in vivo. This combination potentiated tumor growth inhibition in vivo, even in the MM1.S model of myeloma that is not intrinsically sensitive to JAK inhibition alone.</jats:p>
</jats:sec>
<jats:sec>
<jats:title>Conclusions:</jats:title>
<jats:p>Preclinical data reveal insights into vulnerabilities created in myeloma cells by BET protein inhibition and potential strategies that can be leveraged in clinical studies to enhance the activity of INCB054329.</jats:p>
</jats:sec> |
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| author | Stubbs, Matthew C., Burn, Timothy C., Sparks, Richard, Maduskuie, Thomas, Diamond, Sharon, Rupar, Mark, Wen, Xiaoming, Volgina, Alla, Zolotarjova, Nina, Waeltz, Paul, Favata, Margaret, Jalluri, Ravi, Liu, Huiqing, Liu, Xuesong Mike, Li, Jun, Collins, Robert, Falahatpisheh, Nikoo, Polam, Padmaja, DiMatteo, Darlise, Feldman, Patricia, Dostalik, Valerie, Thekkat, Pramod, Gardiner, Christine, He, Xin, Li, Yanlong, Covington, Maryanne, Wynn, Richard, Ruggeri, Bruce, Yeleswaram, Swamy, Xue, Chu-Biao, Yao, Wenqing, Combs, Andrew P., Huber, Reid, Hollis, Gregory, Scherle, Peggy, Liu, Phillip C.C. |
| author_facet | Stubbs, Matthew C., Burn, Timothy C., Sparks, Richard, Maduskuie, Thomas, Diamond, Sharon, Rupar, Mark, Wen, Xiaoming, Volgina, Alla, Zolotarjova, Nina, Waeltz, Paul, Favata, Margaret, Jalluri, Ravi, Liu, Huiqing, Liu, Xuesong Mike, Li, Jun, Collins, Robert, Falahatpisheh, Nikoo, Polam, Padmaja, DiMatteo, Darlise, Feldman, Patricia, Dostalik, Valerie, Thekkat, Pramod, Gardiner, Christine, He, Xin, Li, Yanlong, Covington, Maryanne, Wynn, Richard, Ruggeri, Bruce, Yeleswaram, Swamy, Xue, Chu-Biao, Yao, Wenqing, Combs, Andrew P., Huber, Reid, Hollis, Gregory, Scherle, Peggy, Liu, Phillip C.C., Stubbs, Matthew C., Burn, Timothy C., Sparks, Richard, Maduskuie, Thomas, Diamond, Sharon, Rupar, Mark, Wen, Xiaoming, Volgina, Alla, Zolotarjova, Nina, Waeltz, Paul, Favata, Margaret, Jalluri, Ravi, Liu, Huiqing, Liu, Xuesong Mike, Li, Jun, Collins, Robert, Falahatpisheh, Nikoo, Polam, Padmaja, DiMatteo, Darlise, Feldman, Patricia, Dostalik, Valerie, Thekkat, Pramod, Gardiner, Christine, He, Xin, Li, Yanlong, Covington, Maryanne, Wynn, Richard, Ruggeri, Bruce, Yeleswaram, Swamy, Xue, Chu-Biao, Yao, Wenqing, Combs, Andrew P., Huber, Reid, Hollis, Gregory, Scherle, Peggy, Liu, Phillip C.C. |
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| description | <jats:title>Abstract</jats:title> <jats:sec> <jats:title>Purpose:</jats:title> <jats:p>Bromodomain and extraterminal domain (BET) proteins regulate the expression of many cancer-associated genes and pathways; BET inhibitors have demonstrated activity in diverse models of hematologic and solid tumors. We report the preclinical characterization of INCB054329, a structurally distinct BET inhibitor that has been investigated in phase I clinical trials.</jats:p> </jats:sec> <jats:sec> <jats:title>Experimental Design:</jats:title> <jats:p>We used multiple myeloma models to investigate vulnerabilities created by INCB054329 treatment that could inform rational combinations.</jats:p> </jats:sec> <jats:sec> <jats:title>Results:</jats:title> <jats:p>In addition to c-MYC, INCB054329 decreased expression of oncogenes FGFR3 and NSD2/MMSET/WHSC1, which are deregulated in t(4;14)-rearranged cell lines. The profound suppression of FGFR3 sensitized the t(4;14)-positive cell line OPM-2 to combined treatment with a fibroblast growth factor receptor inhibitor in vivo. In addition, we show that BET inhibition across multiple myeloma cell lines resulted in suppressed interleukin (IL)-6 Janus kinase–signal transducers and activators of transcription (JAK–STAT) signaling. INCB054329 displaced binding of BRD4 to the promoter of IL6 receptor (IL6R) leading to reduced levels of IL6R and diminished signaling through STAT3. Combination with JAK inhibitors (ruxolitinib or itacitinib) further reduced JAK–STAT signaling and synergized to inhibit myeloma cell growth in vitro and in vivo. This combination potentiated tumor growth inhibition in vivo, even in the MM1.S model of myeloma that is not intrinsically sensitive to JAK inhibition alone.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions:</jats:title> <jats:p>Preclinical data reveal insights into vulnerabilities created in myeloma cells by BET protein inhibition and potential strategies that can be leveraged in clinical studies to enhance the activity of INCB054329.</jats:p> </jats:sec> |
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| spelling | Stubbs, Matthew C. Burn, Timothy C. Sparks, Richard Maduskuie, Thomas Diamond, Sharon Rupar, Mark Wen, Xiaoming Volgina, Alla Zolotarjova, Nina Waeltz, Paul Favata, Margaret Jalluri, Ravi Liu, Huiqing Liu, Xuesong Mike Li, Jun Collins, Robert Falahatpisheh, Nikoo Polam, Padmaja DiMatteo, Darlise Feldman, Patricia Dostalik, Valerie Thekkat, Pramod Gardiner, Christine He, Xin Li, Yanlong Covington, Maryanne Wynn, Richard Ruggeri, Bruce Yeleswaram, Swamy Xue, Chu-Biao Yao, Wenqing Combs, Andrew P. Huber, Reid Hollis, Gregory Scherle, Peggy Liu, Phillip C.C. 1078-0432 1557-3265 American Association for Cancer Research (AACR) Cancer Research Oncology http://dx.doi.org/10.1158/1078-0432.ccr-18-0098 <jats:title>Abstract</jats:title> <jats:sec> <jats:title>Purpose:</jats:title> <jats:p>Bromodomain and extraterminal domain (BET) proteins regulate the expression of many cancer-associated genes and pathways; BET inhibitors have demonstrated activity in diverse models of hematologic and solid tumors. We report the preclinical characterization of INCB054329, a structurally distinct BET inhibitor that has been investigated in phase I clinical trials.</jats:p> </jats:sec> <jats:sec> <jats:title>Experimental Design:</jats:title> <jats:p>We used multiple myeloma models to investigate vulnerabilities created by INCB054329 treatment that could inform rational combinations.</jats:p> </jats:sec> <jats:sec> <jats:title>Results:</jats:title> <jats:p>In addition to c-MYC, INCB054329 decreased expression of oncogenes FGFR3 and NSD2/MMSET/WHSC1, which are deregulated in t(4;14)-rearranged cell lines. The profound suppression of FGFR3 sensitized the t(4;14)-positive cell line OPM-2 to combined treatment with a fibroblast growth factor receptor inhibitor in vivo. In addition, we show that BET inhibition across multiple myeloma cell lines resulted in suppressed interleukin (IL)-6 Janus kinase–signal transducers and activators of transcription (JAK–STAT) signaling. INCB054329 displaced binding of BRD4 to the promoter of IL6 receptor (IL6R) leading to reduced levels of IL6R and diminished signaling through STAT3. Combination with JAK inhibitors (ruxolitinib or itacitinib) further reduced JAK–STAT signaling and synergized to inhibit myeloma cell growth in vitro and in vivo. This combination potentiated tumor growth inhibition in vivo, even in the MM1.S model of myeloma that is not intrinsically sensitive to JAK inhibition alone.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions:</jats:title> <jats:p>Preclinical data reveal insights into vulnerabilities created in myeloma cells by BET protein inhibition and potential strategies that can be leveraged in clinical studies to enhance the activity of INCB054329.</jats:p> </jats:sec> The Novel Bromodomain and Extraterminal Domain Inhibitor INCB054329 Induces Vulnerabilities in Myeloma Cells That Inform Rational Combination Strategies Clinical Cancer Research |
| spellingShingle | Stubbs, Matthew C., Burn, Timothy C., Sparks, Richard, Maduskuie, Thomas, Diamond, Sharon, Rupar, Mark, Wen, Xiaoming, Volgina, Alla, Zolotarjova, Nina, Waeltz, Paul, Favata, Margaret, Jalluri, Ravi, Liu, Huiqing, Liu, Xuesong Mike, Li, Jun, Collins, Robert, Falahatpisheh, Nikoo, Polam, Padmaja, DiMatteo, Darlise, Feldman, Patricia, Dostalik, Valerie, Thekkat, Pramod, Gardiner, Christine, He, Xin, Li, Yanlong, Covington, Maryanne, Wynn, Richard, Ruggeri, Bruce, Yeleswaram, Swamy, Xue, Chu-Biao, Yao, Wenqing, Combs, Andrew P., Huber, Reid, Hollis, Gregory, Scherle, Peggy, Liu, Phillip C.C., Clinical Cancer Research, The Novel Bromodomain and Extraterminal Domain Inhibitor INCB054329 Induces Vulnerabilities in Myeloma Cells That Inform Rational Combination Strategies, Cancer Research, Oncology |
| title | The Novel Bromodomain and Extraterminal Domain Inhibitor INCB054329 Induces Vulnerabilities in Myeloma Cells That Inform Rational Combination Strategies |
| title_full | The Novel Bromodomain and Extraterminal Domain Inhibitor INCB054329 Induces Vulnerabilities in Myeloma Cells That Inform Rational Combination Strategies |
| title_fullStr | The Novel Bromodomain and Extraterminal Domain Inhibitor INCB054329 Induces Vulnerabilities in Myeloma Cells That Inform Rational Combination Strategies |
| title_full_unstemmed | The Novel Bromodomain and Extraterminal Domain Inhibitor INCB054329 Induces Vulnerabilities in Myeloma Cells That Inform Rational Combination Strategies |
| title_short | The Novel Bromodomain and Extraterminal Domain Inhibitor INCB054329 Induces Vulnerabilities in Myeloma Cells That Inform Rational Combination Strategies |
| title_sort | the novel bromodomain and extraterminal domain inhibitor incb054329 induces vulnerabilities in myeloma cells that inform rational combination strategies |
| title_unstemmed | The Novel Bromodomain and Extraterminal Domain Inhibitor INCB054329 Induces Vulnerabilities in Myeloma Cells That Inform Rational Combination Strategies |
| topic | Cancer Research, Oncology |
| url | http://dx.doi.org/10.1158/1078-0432.ccr-18-0098 |