Novel BET protein proteolysis-Targeting chimera exerts superior lethal activity than bromodomain inhibitor (BETi) against post-myeloproliferative neoplasm secondary (s) AML cells

D. T. Saenz; W. Fiskus; Y. Qian; T. Manshouri; K. Rajapakshe; K. Raina; K. G. Coleman; A. P. Crew; A. Shen; C. P. Mill; B. Sun; P. Qiu; T. M. Kadia; N. Pemmaraju; C. Dinardo; M. S. Kim; A. J. Nowak; C. Coarfa; C. M. Crews; S. Verstovsek; K. N. Bhalla

doi:10.1038/leu.2016.393

Novel BET protein proteolysis-Targeting chimera exerts superior lethal activity than bromodomain inhibitor (BETi) against post-myeloproliferative neoplasm secondary (s) AML cells

D. T. Saenz, W. Fiskus, Y. Qian, T. Manshouri, K. Rajapakshe, K. Raina, K. G. Coleman, A. P. Crew, A. Shen, C. P. Mill, B. Sun, P. Qiu, T. M. Kadia, N. Pemmaraju, C. Dinardo, M. S. Kim, A. J. Nowak, C. Coarfa, C. M. Crews, S. VerstovsekK. N. Bhalla

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148 Scopus citations

Abstract

The PROTAC (proteolysis-Targeting chimera) ARV-825 recruits bromodomain and extraterminal (BET) proteins to the E3 ubiquitin ligase cereblon, leading to degradation of BET proteins, including BRD4. Although the BET-protein inhibitor (BETi) OTX015 caused accumulation of BRD4, treatment with equimolar concentrations of ARV-825 caused sustained and profound depletion (>90%) of BRD4 and induced significantly more apoptosis in cultured and patient-derived (PD) CD34+ post-MPN sAML cells, while relatively sparing the CD34+ normal hematopoietic progenitor cells. RNA-Seq, Reverse Phase Protein Array and mass cytometry â € CyTOF' analyses demonstrated that ARV-825 caused greater perturbations in messenger RNA (mRNA) and protein expressions than OTX015 in sAML cells. Specifically, compared with OTX015, ARV-825 treatment caused more robust and sustained depletion of c-Myc, CDK4/6, JAK2, p-STAT3/5, PIM1 and Bcl-xL, while increasing the levels of p21 and p27. Compared with OTX015, PROTAC ARV-771 treatment caused greater reduction in leukemia burden and further improved survival of NSG mice engrafted with luciferase-expressing HEL92.1.7 cells. Co-Treatment with ARV-825 and JAK inhibitor ruxolitinib was synergistically lethal against established and PD CD34+ sAML cells. Notably, ARV-825 induced high levels of apoptosis in the in vitro generated ruxolitinib-persister or ruxolitinib-resistant sAML cells. These findings strongly support the in vivo testing of the BRD4-PROTAC based combinations against post-MPN sAML.

Original language	English (US)
Pages (from-to)	1951-1961
Number of pages	11
Journal	Leukemia
Volume	31
Issue number	9
DOIs	https://doi.org/10.1038/leu.2016.393
State	Published - Sep 1 2017

ASJC Scopus subject areas

Hematology
Oncology
Cancer Research

MD Anderson CCSG core facilities

Bioinformatics Shared Resource
Flow Cytometry and Cellular Imaging Facility
Functional Proteomics Reverse Phase Protein Array Core

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Saenz, D. T., Fiskus, W., Qian, Y., Manshouri, T., Rajapakshe, K., Raina, K., Coleman, K. G., Crew, A. P., Shen, A., Mill, C. P., Sun, B., Qiu, P., Kadia, T. M., Pemmaraju, N., Dinardo, C., Kim, M. S., Nowak, A. J., Coarfa, C., Crews, C. M., ... Bhalla, K. N. (2017). Novel BET protein proteolysis-Targeting chimera exerts superior lethal activity than bromodomain inhibitor (BETi) against post-myeloproliferative neoplasm secondary (s) AML cells. Leukemia, 31(9), 1951-1961. https://doi.org/10.1038/leu.2016.393

Saenz, DT, Fiskus, W, Qian, Y, Manshouri, T, Rajapakshe, K, Raina, K, Coleman, KG, Crew, AP, Shen, A, Mill, CP , Sun, B, Qiu, P, Kadia, TM , Pemmaraju, N , Dinardo, C , Kim, MS, Nowak, AJ, Coarfa, C, Crews, CM, Verstovsek, S & Bhalla, KN 2017, 'Novel BET protein proteolysis-Targeting chimera exerts superior lethal activity than bromodomain inhibitor (BETi) against post-myeloproliferative neoplasm secondary (s) AML cells', Leukemia, vol. 31, no. 9, pp. 1951-1961. https://doi.org/10.1038/leu.2016.393

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title = "Novel BET protein proteolysis-Targeting chimera exerts superior lethal activity than bromodomain inhibitor (BETi) against post-myeloproliferative neoplasm secondary (s) AML cells",

abstract = "The PROTAC (proteolysis-Targeting chimera) ARV-825 recruits bromodomain and extraterminal (BET) proteins to the E3 ubiquitin ligase cereblon, leading to degradation of BET proteins, including BRD4. Although the BET-protein inhibitor (BETi) OTX015 caused accumulation of BRD4, treatment with equimolar concentrations of ARV-825 caused sustained and profound depletion (>90%) of BRD4 and induced significantly more apoptosis in cultured and patient-derived (PD) CD34+ post-MPN sAML cells, while relatively sparing the CD34+ normal hematopoietic progenitor cells. RNA-Seq, Reverse Phase Protein Array and mass cytometry {\^a} € CyTOF' analyses demonstrated that ARV-825 caused greater perturbations in messenger RNA (mRNA) and protein expressions than OTX015 in sAML cells. Specifically, compared with OTX015, ARV-825 treatment caused more robust and sustained depletion of c-Myc, CDK4/6, JAK2, p-STAT3/5, PIM1 and Bcl-xL, while increasing the levels of p21 and p27. Compared with OTX015, PROTAC ARV-771 treatment caused greater reduction in leukemia burden and further improved survival of NSG mice engrafted with luciferase-expressing HEL92.1.7 cells. Co-Treatment with ARV-825 and JAK inhibitor ruxolitinib was synergistically lethal against established and PD CD34+ sAML cells. Notably, ARV-825 induced high levels of apoptosis in the in vitro generated ruxolitinib-persister or ruxolitinib-resistant sAML cells. These findings strongly support the in vivo testing of the BRD4-PROTAC based combinations against post-MPN sAML.",

author = "Saenz, {D. T.} and W. Fiskus and Y. Qian and T. Manshouri and K. Rajapakshe and K. Raina and Coleman, {K. G.} and Crew, {A. P.} and A. Shen and Mill, {C. P.} and B. Sun and P. Qiu and Kadia, {T. M.} and N. Pemmaraju and C. Dinardo and Kim, {M. S.} and Nowak, {A. J.} and C. Coarfa and Crews, {C. M.} and S. Verstovsek and Bhalla, {K. N.}",

note = "Publisher Copyright: {\textcopyright} 2017 Macmillan Publishers Limited, part of Springer Nature.",

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doi = "10.1038/leu.2016.393",

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T1 - Novel BET protein proteolysis-Targeting chimera exerts superior lethal activity than bromodomain inhibitor (BETi) against post-myeloproliferative neoplasm secondary (s) AML cells

AU - Saenz, D. T.

AU - Fiskus, W.

AU - Qian, Y.

AU - Manshouri, T.

AU - Rajapakshe, K.

AU - Raina, K.

AU - Coleman, K. G.

AU - Crew, A. P.

AU - Shen, A.

AU - Mill, C. P.

AU - Sun, B.

AU - Qiu, P.

AU - Kadia, T. M.

AU - Pemmaraju, N.

AU - Dinardo, C.

AU - Kim, M. S.

AU - Nowak, A. J.

AU - Coarfa, C.

AU - Crews, C. M.

AU - Verstovsek, S.

AU - Bhalla, K. N.

PY - 2017/9/1

Y1 - 2017/9/1

N2 - The PROTAC (proteolysis-Targeting chimera) ARV-825 recruits bromodomain and extraterminal (BET) proteins to the E3 ubiquitin ligase cereblon, leading to degradation of BET proteins, including BRD4. Although the BET-protein inhibitor (BETi) OTX015 caused accumulation of BRD4, treatment with equimolar concentrations of ARV-825 caused sustained and profound depletion (>90%) of BRD4 and induced significantly more apoptosis in cultured and patient-derived (PD) CD34+ post-MPN sAML cells, while relatively sparing the CD34+ normal hematopoietic progenitor cells. RNA-Seq, Reverse Phase Protein Array and mass cytometry â € CyTOF' analyses demonstrated that ARV-825 caused greater perturbations in messenger RNA (mRNA) and protein expressions than OTX015 in sAML cells. Specifically, compared with OTX015, ARV-825 treatment caused more robust and sustained depletion of c-Myc, CDK4/6, JAK2, p-STAT3/5, PIM1 and Bcl-xL, while increasing the levels of p21 and p27. Compared with OTX015, PROTAC ARV-771 treatment caused greater reduction in leukemia burden and further improved survival of NSG mice engrafted with luciferase-expressing HEL92.1.7 cells. Co-Treatment with ARV-825 and JAK inhibitor ruxolitinib was synergistically lethal against established and PD CD34+ sAML cells. Notably, ARV-825 induced high levels of apoptosis in the in vitro generated ruxolitinib-persister or ruxolitinib-resistant sAML cells. These findings strongly support the in vivo testing of the BRD4-PROTAC based combinations against post-MPN sAML.

AB - The PROTAC (proteolysis-Targeting chimera) ARV-825 recruits bromodomain and extraterminal (BET) proteins to the E3 ubiquitin ligase cereblon, leading to degradation of BET proteins, including BRD4. Although the BET-protein inhibitor (BETi) OTX015 caused accumulation of BRD4, treatment with equimolar concentrations of ARV-825 caused sustained and profound depletion (>90%) of BRD4 and induced significantly more apoptosis in cultured and patient-derived (PD) CD34+ post-MPN sAML cells, while relatively sparing the CD34+ normal hematopoietic progenitor cells. RNA-Seq, Reverse Phase Protein Array and mass cytometry â € CyTOF' analyses demonstrated that ARV-825 caused greater perturbations in messenger RNA (mRNA) and protein expressions than OTX015 in sAML cells. Specifically, compared with OTX015, ARV-825 treatment caused more robust and sustained depletion of c-Myc, CDK4/6, JAK2, p-STAT3/5, PIM1 and Bcl-xL, while increasing the levels of p21 and p27. Compared with OTX015, PROTAC ARV-771 treatment caused greater reduction in leukemia burden and further improved survival of NSG mice engrafted with luciferase-expressing HEL92.1.7 cells. Co-Treatment with ARV-825 and JAK inhibitor ruxolitinib was synergistically lethal against established and PD CD34+ sAML cells. Notably, ARV-825 induced high levels of apoptosis in the in vitro generated ruxolitinib-persister or ruxolitinib-resistant sAML cells. These findings strongly support the in vivo testing of the BRD4-PROTAC based combinations against post-MPN sAML.

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Novel BET protein proteolysis-Targeting chimera exerts superior lethal activity than bromodomain inhibitor (BETi) against post-myeloproliferative neoplasm secondary (s) AML cells

Abstract

ASJC Scopus subject areas

MD Anderson CCSG core facilities

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