Targeting acute myeloid leukemia by dual inhibition of PI3K signaling and Cdk9-mediated Mcl-1 transcription

Daniel Thomas, Jason A Powell, Francois Vergez, David Segal, Nhu-Y N Nguyen, Adele Baker, Tse-Chieh Teh, Emma F Barry, Jean-Emmanuel Sarry, Erwin M Lee, Tracy L Nero, Anissa M Jabbour, Giovanna Pomilio, Benjamin D Green, Stephane Manenti, Stefan P Glaser, Michael William Parker, Angel F Lopez, Paul G Ekert, Richard B Lock & 5 others David CS Huang, Susan Kay Nilsson, Christian Recher, Andrew Wei, Mark Andrew Guthridge

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Resistance to cell death is a hallmark of cancer and renders transformed cells resistant to multiple apoptotic triggers. The Bcl-2 family member, Mcl-1, is a key driver of cell survival in diverse cancers, including acute myeloid leukemia (AML). A screen for compounds that downregulate Mcl-1 identified the kinase inhibitor, PIK-75, which demonstrates marked proapoptotic activity against a panel of cytogenetically diverse primary human AML patient samples. We show that PIK-75 transiently blocks Cdk7/9, leading to transcriptional suppression of MCL-1, rapid loss of Mcl-1 protein, and alleviation of its inhibition of proapoptotic Bak. PIK-75 also targets the p110a isoform of PI3K, which leads to a loss of association between Bcl-xL and Bak. The simultaneous loss of Mcl-1 and Bcl-xL association with Bak leads to rapid apoptosis of AML cells. Concordantly, low Bak expression in AML confers resistance to PIK-75-mediated killing. On the other hand, the induction of apoptosis by PIK-75 did not require the expression of the BH3 proteins Bim, Bid, Bad, Noxa, or Puma. PIK-75 significantly reduced leukemia burden and increased the survival of mice engrafted with human AML without inducing overt toxicity. Future efforts to cotarget PI3K and Cdk9 with drugs such as PIK-75 in AML are warranted.
Original languageEnglish
Pages (from-to)738 - 748
Number of pages11
JournalBlood
Volume122
Issue number5
DOIs
Publication statusPublished - 2013

Cite this

Thomas, D., Powell, J. A., Vergez, F., Segal, D., Nguyen, N-Y. N., Baker, A., ... Guthridge, M. A. (2013). Targeting acute myeloid leukemia by dual inhibition of PI3K signaling and Cdk9-mediated Mcl-1 transcription. Blood, 122(5), 738 - 748. https://doi.org/10.1182/blood-2012-08-447441
Thomas, Daniel ; Powell, Jason A ; Vergez, Francois ; Segal, David ; Nguyen, Nhu-Y N ; Baker, Adele ; Teh, Tse-Chieh ; Barry, Emma F ; Sarry, Jean-Emmanuel ; Lee, Erwin M ; Nero, Tracy L ; Jabbour, Anissa M ; Pomilio, Giovanna ; Green, Benjamin D ; Manenti, Stephane ; Glaser, Stefan P ; Parker, Michael William ; Lopez, Angel F ; Ekert, Paul G ; Lock, Richard B ; Huang, David CS ; Nilsson, Susan Kay ; Recher, Christian ; Wei, Andrew ; Guthridge, Mark Andrew. / Targeting acute myeloid leukemia by dual inhibition of PI3K signaling and Cdk9-mediated Mcl-1 transcription. In: Blood. 2013 ; Vol. 122, No. 5. pp. 738 - 748.
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title = "Targeting acute myeloid leukemia by dual inhibition of PI3K signaling and Cdk9-mediated Mcl-1 transcription",
abstract = "Resistance to cell death is a hallmark of cancer and renders transformed cells resistant to multiple apoptotic triggers. The Bcl-2 family member, Mcl-1, is a key driver of cell survival in diverse cancers, including acute myeloid leukemia (AML). A screen for compounds that downregulate Mcl-1 identified the kinase inhibitor, PIK-75, which demonstrates marked proapoptotic activity against a panel of cytogenetically diverse primary human AML patient samples. We show that PIK-75 transiently blocks Cdk7/9, leading to transcriptional suppression of MCL-1, rapid loss of Mcl-1 protein, and alleviation of its inhibition of proapoptotic Bak. PIK-75 also targets the p110a isoform of PI3K, which leads to a loss of association between Bcl-xL and Bak. The simultaneous loss of Mcl-1 and Bcl-xL association with Bak leads to rapid apoptosis of AML cells. Concordantly, low Bak expression in AML confers resistance to PIK-75-mediated killing. On the other hand, the induction of apoptosis by PIK-75 did not require the expression of the BH3 proteins Bim, Bid, Bad, Noxa, or Puma. PIK-75 significantly reduced leukemia burden and increased the survival of mice engrafted with human AML without inducing overt toxicity. Future efforts to cotarget PI3K and Cdk9 with drugs such as PIK-75 in AML are warranted.",
author = "Daniel Thomas and Powell, {Jason A} and Francois Vergez and David Segal and Nguyen, {Nhu-Y N} and Adele Baker and Tse-Chieh Teh and Barry, {Emma F} and Jean-Emmanuel Sarry and Lee, {Erwin M} and Nero, {Tracy L} and Jabbour, {Anissa M} and Giovanna Pomilio and Green, {Benjamin D} and Stephane Manenti and Glaser, {Stefan P} and Parker, {Michael William} and Lopez, {Angel F} and Ekert, {Paul G} and Lock, {Richard B} and Huang, {David CS} and Nilsson, {Susan Kay} and Christian Recher and Andrew Wei and Guthridge, {Mark Andrew}",
year = "2013",
doi = "10.1182/blood-2012-08-447441",
language = "English",
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Thomas, D, Powell, JA, Vergez, F, Segal, D, Nguyen, N-YN, Baker, A, Teh, T-C, Barry, EF, Sarry, J-E, Lee, EM, Nero, TL, Jabbour, AM, Pomilio, G, Green, BD, Manenti, S, Glaser, SP, Parker, MW, Lopez, AF, Ekert, PG, Lock, RB, Huang, DCS, Nilsson, SK, Recher, C, Wei, A & Guthridge, MA 2013, 'Targeting acute myeloid leukemia by dual inhibition of PI3K signaling and Cdk9-mediated Mcl-1 transcription', Blood, vol. 122, no. 5, pp. 738 - 748. https://doi.org/10.1182/blood-2012-08-447441

Targeting acute myeloid leukemia by dual inhibition of PI3K signaling and Cdk9-mediated Mcl-1 transcription. / Thomas, Daniel; Powell, Jason A; Vergez, Francois; Segal, David; Nguyen, Nhu-Y N; Baker, Adele; Teh, Tse-Chieh; Barry, Emma F; Sarry, Jean-Emmanuel; Lee, Erwin M; Nero, Tracy L; Jabbour, Anissa M; Pomilio, Giovanna; Green, Benjamin D; Manenti, Stephane; Glaser, Stefan P; Parker, Michael William; Lopez, Angel F; Ekert, Paul G; Lock, Richard B; Huang, David CS; Nilsson, Susan Kay; Recher, Christian; Wei, Andrew; Guthridge, Mark Andrew.

In: Blood, Vol. 122, No. 5, 2013, p. 738 - 748.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Targeting acute myeloid leukemia by dual inhibition of PI3K signaling and Cdk9-mediated Mcl-1 transcription

AU - Thomas, Daniel

AU - Powell, Jason A

AU - Vergez, Francois

AU - Segal, David

AU - Nguyen, Nhu-Y N

AU - Baker, Adele

AU - Teh, Tse-Chieh

AU - Barry, Emma F

AU - Sarry, Jean-Emmanuel

AU - Lee, Erwin M

AU - Nero, Tracy L

AU - Jabbour, Anissa M

AU - Pomilio, Giovanna

AU - Green, Benjamin D

AU - Manenti, Stephane

AU - Glaser, Stefan P

AU - Parker, Michael William

AU - Lopez, Angel F

AU - Ekert, Paul G

AU - Lock, Richard B

AU - Huang, David CS

AU - Nilsson, Susan Kay

AU - Recher, Christian

AU - Wei, Andrew

AU - Guthridge, Mark Andrew

PY - 2013

Y1 - 2013

N2 - Resistance to cell death is a hallmark of cancer and renders transformed cells resistant to multiple apoptotic triggers. The Bcl-2 family member, Mcl-1, is a key driver of cell survival in diverse cancers, including acute myeloid leukemia (AML). A screen for compounds that downregulate Mcl-1 identified the kinase inhibitor, PIK-75, which demonstrates marked proapoptotic activity against a panel of cytogenetically diverse primary human AML patient samples. We show that PIK-75 transiently blocks Cdk7/9, leading to transcriptional suppression of MCL-1, rapid loss of Mcl-1 protein, and alleviation of its inhibition of proapoptotic Bak. PIK-75 also targets the p110a isoform of PI3K, which leads to a loss of association between Bcl-xL and Bak. The simultaneous loss of Mcl-1 and Bcl-xL association with Bak leads to rapid apoptosis of AML cells. Concordantly, low Bak expression in AML confers resistance to PIK-75-mediated killing. On the other hand, the induction of apoptosis by PIK-75 did not require the expression of the BH3 proteins Bim, Bid, Bad, Noxa, or Puma. PIK-75 significantly reduced leukemia burden and increased the survival of mice engrafted with human AML without inducing overt toxicity. Future efforts to cotarget PI3K and Cdk9 with drugs such as PIK-75 in AML are warranted.

AB - Resistance to cell death is a hallmark of cancer and renders transformed cells resistant to multiple apoptotic triggers. The Bcl-2 family member, Mcl-1, is a key driver of cell survival in diverse cancers, including acute myeloid leukemia (AML). A screen for compounds that downregulate Mcl-1 identified the kinase inhibitor, PIK-75, which demonstrates marked proapoptotic activity against a panel of cytogenetically diverse primary human AML patient samples. We show that PIK-75 transiently blocks Cdk7/9, leading to transcriptional suppression of MCL-1, rapid loss of Mcl-1 protein, and alleviation of its inhibition of proapoptotic Bak. PIK-75 also targets the p110a isoform of PI3K, which leads to a loss of association between Bcl-xL and Bak. The simultaneous loss of Mcl-1 and Bcl-xL association with Bak leads to rapid apoptosis of AML cells. Concordantly, low Bak expression in AML confers resistance to PIK-75-mediated killing. On the other hand, the induction of apoptosis by PIK-75 did not require the expression of the BH3 proteins Bim, Bid, Bad, Noxa, or Puma. PIK-75 significantly reduced leukemia burden and increased the survival of mice engrafted with human AML without inducing overt toxicity. Future efforts to cotarget PI3K and Cdk9 with drugs such as PIK-75 in AML are warranted.

UR - http://bloodjournal.hematologylibrary.org/content/122/5/738.full.pdf

U2 - 10.1182/blood-2012-08-447441

DO - 10.1182/blood-2012-08-447441

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