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Inhibition of Hsp90 Suppresses PI3K/AKT/mTOR Signaling and Has Antitumor Activity in Burkitt Lymphoma
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| Zeitschriftentitel: | Molecular Cancer Therapeutics |
|---|---|
| Personen und Körperschaften: | , , , , , , , , , , , , , , , |
| In: | Molecular Cancer Therapeutics, 16, 2017, 9, S. 1779-1790 |
| Format: | E-Article |
| Sprache: | Englisch |
| veröffentlicht: |
American Association for Cancer Research (AACR)
|
| Schlagwörter: |
| author_facet |
Giulino-Roth, Lisa van Besien, Herman J. Dalton, Tanner Totonchy, Jennifer E. Rodina, Anna Taldone, Tony Bolaender, Alexander Erdjument-Bromage, Hediye Sadek, Jouliana Chadburn, Amy Barth, Matthew J. Dela Cruz, Filemon S. Rainey, Allison Kung, Andrew L. Chiosis, Gabriela Cesarman, Ethel Giulino-Roth, Lisa van Besien, Herman J. Dalton, Tanner Totonchy, Jennifer E. Rodina, Anna Taldone, Tony Bolaender, Alexander Erdjument-Bromage, Hediye Sadek, Jouliana Chadburn, Amy Barth, Matthew J. Dela Cruz, Filemon S. Rainey, Allison Kung, Andrew L. Chiosis, Gabriela Cesarman, Ethel |
|---|---|
| author |
Giulino-Roth, Lisa van Besien, Herman J. Dalton, Tanner Totonchy, Jennifer E. Rodina, Anna Taldone, Tony Bolaender, Alexander Erdjument-Bromage, Hediye Sadek, Jouliana Chadburn, Amy Barth, Matthew J. Dela Cruz, Filemon S. Rainey, Allison Kung, Andrew L. Chiosis, Gabriela Cesarman, Ethel |
| spellingShingle |
Giulino-Roth, Lisa van Besien, Herman J. Dalton, Tanner Totonchy, Jennifer E. Rodina, Anna Taldone, Tony Bolaender, Alexander Erdjument-Bromage, Hediye Sadek, Jouliana Chadburn, Amy Barth, Matthew J. Dela Cruz, Filemon S. Rainey, Allison Kung, Andrew L. Chiosis, Gabriela Cesarman, Ethel Molecular Cancer Therapeutics Inhibition of Hsp90 Suppresses PI3K/AKT/mTOR Signaling and Has Antitumor Activity in Burkitt Lymphoma Cancer Research Oncology |
| author_sort |
giulino-roth, lisa |
| spelling |
Giulino-Roth, Lisa van Besien, Herman J. Dalton, Tanner Totonchy, Jennifer E. Rodina, Anna Taldone, Tony Bolaender, Alexander Erdjument-Bromage, Hediye Sadek, Jouliana Chadburn, Amy Barth, Matthew J. Dela Cruz, Filemon S. Rainey, Allison Kung, Andrew L. Chiosis, Gabriela Cesarman, Ethel 1535-7163 1538-8514 American Association for Cancer Research (AACR) Cancer Research Oncology http://dx.doi.org/10.1158/1535-7163.mct-16-0848 <jats:title>Abstract</jats:title> <jats:p>Hsp90 is a molecular chaperone that protects proteins, including oncogenic signaling complexes, from proteolytic degradation. PU-H71 is a next-generation Hsp90 inhibitor that preferentially targets the functionally distinct pool of Hsp90 present in tumor cells. Tumors that are driven by the MYC oncoprotein may be particularly sensitive to PU-H71 due to the essential role of Hsp90 in the epichaperome, which maintains the malignant phenotype in the setting of MYC. Burkitt lymphoma (BL) is an aggressive B-cell lymphoma characterized by MYC dysregulation. In this study, we evaluated Hsp90 as a potential therapeutic target in BL. We found that primary BL tumors overexpress Hsp90 and that Hsp90 inhibition has antitumor activity in vitro and in vivo, including potent activity in a patient-derived xenograft model of BL. To evaluate the targets of PU-H71 in BL, we performed high-affinity capture followed by proteomic analysis using mass spectrometry. We found that Hsp90 inhibition targets multiple components of PI3K/AKT/mTOR signaling, highlighting the importance of this pathway in BL. Finally, we found that the anti-lymphoma activity of PU-H71 is synergistic with dual PI3K/mTOR inhibition in vitro and in vivo. Overall, this work provides support for Hsp90 as a therapeutic target in BL and suggests the potential for combination therapy with PU-H71 and inhibitors of PI3K/mTOR. Mol Cancer Ther; 16(9); 1779–90. ©2017 AACR.</jats:p> Inhibition of Hsp90 Suppresses PI3K/AKT/mTOR Signaling and Has Antitumor Activity in Burkitt Lymphoma Molecular Cancer Therapeutics |
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American Association for Cancer Research (AACR), 2017 |
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American Association for Cancer Research (AACR), 2017 |
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Molecular Cancer Therapeutics |
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| title |
Inhibition of Hsp90 Suppresses PI3K/AKT/mTOR Signaling and Has Antitumor Activity in Burkitt Lymphoma |
| title_unstemmed |
Inhibition of Hsp90 Suppresses PI3K/AKT/mTOR Signaling and Has Antitumor Activity in Burkitt Lymphoma |
| title_full |
Inhibition of Hsp90 Suppresses PI3K/AKT/mTOR Signaling and Has Antitumor Activity in Burkitt Lymphoma |
| title_fullStr |
Inhibition of Hsp90 Suppresses PI3K/AKT/mTOR Signaling and Has Antitumor Activity in Burkitt Lymphoma |
| title_full_unstemmed |
Inhibition of Hsp90 Suppresses PI3K/AKT/mTOR Signaling and Has Antitumor Activity in Burkitt Lymphoma |
| title_short |
Inhibition of Hsp90 Suppresses PI3K/AKT/mTOR Signaling and Has Antitumor Activity in Burkitt Lymphoma |
| title_sort |
inhibition of hsp90 suppresses pi3k/akt/mtor signaling and has antitumor activity in burkitt lymphoma |
| topic |
Cancer Research Oncology |
| url |
http://dx.doi.org/10.1158/1535-7163.mct-16-0848 |
| publishDate |
2017 |
| physical |
1779-1790 |
| description |
<jats:title>Abstract</jats:title>
<jats:p>Hsp90 is a molecular chaperone that protects proteins, including oncogenic signaling complexes, from proteolytic degradation. PU-H71 is a next-generation Hsp90 inhibitor that preferentially targets the functionally distinct pool of Hsp90 present in tumor cells. Tumors that are driven by the MYC oncoprotein may be particularly sensitive to PU-H71 due to the essential role of Hsp90 in the epichaperome, which maintains the malignant phenotype in the setting of MYC. Burkitt lymphoma (BL) is an aggressive B-cell lymphoma characterized by MYC dysregulation. In this study, we evaluated Hsp90 as a potential therapeutic target in BL. We found that primary BL tumors overexpress Hsp90 and that Hsp90 inhibition has antitumor activity in vitro and in vivo, including potent activity in a patient-derived xenograft model of BL. To evaluate the targets of PU-H71 in BL, we performed high-affinity capture followed by proteomic analysis using mass spectrometry. We found that Hsp90 inhibition targets multiple components of PI3K/AKT/mTOR signaling, highlighting the importance of this pathway in BL. Finally, we found that the anti-lymphoma activity of PU-H71 is synergistic with dual PI3K/mTOR inhibition in vitro and in vivo. Overall, this work provides support for Hsp90 as a therapeutic target in BL and suggests the potential for combination therapy with PU-H71 and inhibitors of PI3K/mTOR. Mol Cancer Ther; 16(9); 1779–90. ©2017 AACR.</jats:p> |
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| author | Giulino-Roth, Lisa, van Besien, Herman J., Dalton, Tanner, Totonchy, Jennifer E., Rodina, Anna, Taldone, Tony, Bolaender, Alexander, Erdjument-Bromage, Hediye, Sadek, Jouliana, Chadburn, Amy, Barth, Matthew J., Dela Cruz, Filemon S., Rainey, Allison, Kung, Andrew L., Chiosis, Gabriela, Cesarman, Ethel |
| author_facet | Giulino-Roth, Lisa, van Besien, Herman J., Dalton, Tanner, Totonchy, Jennifer E., Rodina, Anna, Taldone, Tony, Bolaender, Alexander, Erdjument-Bromage, Hediye, Sadek, Jouliana, Chadburn, Amy, Barth, Matthew J., Dela Cruz, Filemon S., Rainey, Allison, Kung, Andrew L., Chiosis, Gabriela, Cesarman, Ethel, Giulino-Roth, Lisa, van Besien, Herman J., Dalton, Tanner, Totonchy, Jennifer E., Rodina, Anna, Taldone, Tony, Bolaender, Alexander, Erdjument-Bromage, Hediye, Sadek, Jouliana, Chadburn, Amy, Barth, Matthew J., Dela Cruz, Filemon S., Rainey, Allison, Kung, Andrew L., Chiosis, Gabriela, Cesarman, Ethel |
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| description | <jats:title>Abstract</jats:title> <jats:p>Hsp90 is a molecular chaperone that protects proteins, including oncogenic signaling complexes, from proteolytic degradation. PU-H71 is a next-generation Hsp90 inhibitor that preferentially targets the functionally distinct pool of Hsp90 present in tumor cells. Tumors that are driven by the MYC oncoprotein may be particularly sensitive to PU-H71 due to the essential role of Hsp90 in the epichaperome, which maintains the malignant phenotype in the setting of MYC. Burkitt lymphoma (BL) is an aggressive B-cell lymphoma characterized by MYC dysregulation. In this study, we evaluated Hsp90 as a potential therapeutic target in BL. We found that primary BL tumors overexpress Hsp90 and that Hsp90 inhibition has antitumor activity in vitro and in vivo, including potent activity in a patient-derived xenograft model of BL. To evaluate the targets of PU-H71 in BL, we performed high-affinity capture followed by proteomic analysis using mass spectrometry. We found that Hsp90 inhibition targets multiple components of PI3K/AKT/mTOR signaling, highlighting the importance of this pathway in BL. Finally, we found that the anti-lymphoma activity of PU-H71 is synergistic with dual PI3K/mTOR inhibition in vitro and in vivo. Overall, this work provides support for Hsp90 as a therapeutic target in BL and suggests the potential for combination therapy with PU-H71 and inhibitors of PI3K/mTOR. Mol Cancer Ther; 16(9); 1779–90. ©2017 AACR.</jats:p> |
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| spelling | Giulino-Roth, Lisa van Besien, Herman J. Dalton, Tanner Totonchy, Jennifer E. Rodina, Anna Taldone, Tony Bolaender, Alexander Erdjument-Bromage, Hediye Sadek, Jouliana Chadburn, Amy Barth, Matthew J. Dela Cruz, Filemon S. Rainey, Allison Kung, Andrew L. Chiosis, Gabriela Cesarman, Ethel 1535-7163 1538-8514 American Association for Cancer Research (AACR) Cancer Research Oncology http://dx.doi.org/10.1158/1535-7163.mct-16-0848 <jats:title>Abstract</jats:title> <jats:p>Hsp90 is a molecular chaperone that protects proteins, including oncogenic signaling complexes, from proteolytic degradation. PU-H71 is a next-generation Hsp90 inhibitor that preferentially targets the functionally distinct pool of Hsp90 present in tumor cells. Tumors that are driven by the MYC oncoprotein may be particularly sensitive to PU-H71 due to the essential role of Hsp90 in the epichaperome, which maintains the malignant phenotype in the setting of MYC. Burkitt lymphoma (BL) is an aggressive B-cell lymphoma characterized by MYC dysregulation. In this study, we evaluated Hsp90 as a potential therapeutic target in BL. We found that primary BL tumors overexpress Hsp90 and that Hsp90 inhibition has antitumor activity in vitro and in vivo, including potent activity in a patient-derived xenograft model of BL. To evaluate the targets of PU-H71 in BL, we performed high-affinity capture followed by proteomic analysis using mass spectrometry. We found that Hsp90 inhibition targets multiple components of PI3K/AKT/mTOR signaling, highlighting the importance of this pathway in BL. Finally, we found that the anti-lymphoma activity of PU-H71 is synergistic with dual PI3K/mTOR inhibition in vitro and in vivo. Overall, this work provides support for Hsp90 as a therapeutic target in BL and suggests the potential for combination therapy with PU-H71 and inhibitors of PI3K/mTOR. Mol Cancer Ther; 16(9); 1779–90. ©2017 AACR.</jats:p> Inhibition of Hsp90 Suppresses PI3K/AKT/mTOR Signaling and Has Antitumor Activity in Burkitt Lymphoma Molecular Cancer Therapeutics |
| spellingShingle | Giulino-Roth, Lisa, van Besien, Herman J., Dalton, Tanner, Totonchy, Jennifer E., Rodina, Anna, Taldone, Tony, Bolaender, Alexander, Erdjument-Bromage, Hediye, Sadek, Jouliana, Chadburn, Amy, Barth, Matthew J., Dela Cruz, Filemon S., Rainey, Allison, Kung, Andrew L., Chiosis, Gabriela, Cesarman, Ethel, Molecular Cancer Therapeutics, Inhibition of Hsp90 Suppresses PI3K/AKT/mTOR Signaling and Has Antitumor Activity in Burkitt Lymphoma, Cancer Research, Oncology |
| title | Inhibition of Hsp90 Suppresses PI3K/AKT/mTOR Signaling and Has Antitumor Activity in Burkitt Lymphoma |
| title_full | Inhibition of Hsp90 Suppresses PI3K/AKT/mTOR Signaling and Has Antitumor Activity in Burkitt Lymphoma |
| title_fullStr | Inhibition of Hsp90 Suppresses PI3K/AKT/mTOR Signaling and Has Antitumor Activity in Burkitt Lymphoma |
| title_full_unstemmed | Inhibition of Hsp90 Suppresses PI3K/AKT/mTOR Signaling and Has Antitumor Activity in Burkitt Lymphoma |
| title_short | Inhibition of Hsp90 Suppresses PI3K/AKT/mTOR Signaling and Has Antitumor Activity in Burkitt Lymphoma |
| title_sort | inhibition of hsp90 suppresses pi3k/akt/mtor signaling and has antitumor activity in burkitt lymphoma |
| title_unstemmed | Inhibition of Hsp90 Suppresses PI3K/AKT/mTOR Signaling and Has Antitumor Activity in Burkitt Lymphoma |
| topic | Cancer Research, Oncology |
| url | http://dx.doi.org/10.1158/1535-7163.mct-16-0848 |