Enhancing venetoclax activity in acute myeloid leukemia by co-targeting MCL1

T. C. Teh, N. Y. Nguyen, D. M. Moujalled, D. Segal, G. Pomilio, S. Rijal, A. Jabbour, K. Cummins, K. Lackovic, P. Blombery, E. Thompson, P. G. Ekert, G. Lessene, S. P. Glaser, D. C.S. Huang, A. W. Roberts, M. A. Guthridge, A. H. Wei

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Targeted therapies are frequently combined with standard cytotoxic drugs to enhance clinical response. Targeting the B-cell lymphoma 2 (BCL-2) family of proteins is an attractive option to combat chemoresistance in leukemia. Preclinical and clinical studies indicate modest single-agent activity with selective BCL-2 inhibitors (for example, venetoclax). We show that venetoclax synergizes with cytarabine and idarubicin to increase antileukemic efficacy in a TP53-dependent manner. Although TP53 deficiency impaired sensitivity to combined venetoclax and chemotherapy, higher-dose idarubicin was able to suppress MCL1 and induce cell death independently of TP53. Consistent with an MCL1-specific effect, cell death from high-dose idarubicin was dependent on proapoptotic Bak. Combining higher-dose idarubicin with venetoclax was able to partially overcome resistance in Bak-deficient cells. Using inducible vectors and venetoclax to differentially target anti-apoptotic BCL-2 family members, BCL-2 and MCL1 emerged as critical and complementary proteins regulating cell survival in acute myeloid leukemia. Dual targeting of BCL-2 and MCL1, but not either alone, prolonged survival of leukemia-bearing mice. In conclusion, our findings support the further investigation of venetoclax in combination with standard chemotherapy, including intensified doses of idarubicin. Venetoclax should also be investigated in combination with direct inhibitors of MCL1 as a chemotherapy-free approach in the future.

Original languageEnglish
Pages (from-to)303-312
Number of pages10
JournalLeukemia
Volume32
Issue number2
DOIs
Publication statusPublished - 1 Feb 2018

Cite this

Teh, T. C. ; Nguyen, N. Y. ; Moujalled, D. M. ; Segal, D. ; Pomilio, G. ; Rijal, S. ; Jabbour, A. ; Cummins, K. ; Lackovic, K. ; Blombery, P. ; Thompson, E. ; Ekert, P. G. ; Lessene, G. ; Glaser, S. P. ; Huang, D. C.S. ; Roberts, A. W. ; Guthridge, M. A. ; Wei, A. H. / Enhancing venetoclax activity in acute myeloid leukemia by co-targeting MCL1. In: Leukemia. 2018 ; Vol. 32, No. 2. pp. 303-312.
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abstract = "Targeted therapies are frequently combined with standard cytotoxic drugs to enhance clinical response. Targeting the B-cell lymphoma 2 (BCL-2) family of proteins is an attractive option to combat chemoresistance in leukemia. Preclinical and clinical studies indicate modest single-agent activity with selective BCL-2 inhibitors (for example, venetoclax). We show that venetoclax synergizes with cytarabine and idarubicin to increase antileukemic efficacy in a TP53-dependent manner. Although TP53 deficiency impaired sensitivity to combined venetoclax and chemotherapy, higher-dose idarubicin was able to suppress MCL1 and induce cell death independently of TP53. Consistent with an MCL1-specific effect, cell death from high-dose idarubicin was dependent on proapoptotic Bak. Combining higher-dose idarubicin with venetoclax was able to partially overcome resistance in Bak-deficient cells. Using inducible vectors and venetoclax to differentially target anti-apoptotic BCL-2 family members, BCL-2 and MCL1 emerged as critical and complementary proteins regulating cell survival in acute myeloid leukemia. Dual targeting of BCL-2 and MCL1, but not either alone, prolonged survival of leukemia-bearing mice. In conclusion, our findings support the further investigation of venetoclax in combination with standard chemotherapy, including intensified doses of idarubicin. Venetoclax should also be investigated in combination with direct inhibitors of MCL1 as a chemotherapy-free approach in the future.",
author = "Teh, {T. C.} and Nguyen, {N. Y.} and Moujalled, {D. M.} and D. Segal and G. Pomilio and S. Rijal and A. Jabbour and K. Cummins and K. Lackovic and P. Blombery and E. Thompson and Ekert, {P. G.} and G. Lessene and Glaser, {S. P.} and Huang, {D. C.S.} and Roberts, {A. W.} and Guthridge, {M. A.} and Wei, {A. H.}",
year = "2018",
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Teh, TC, Nguyen, NY, Moujalled, DM, Segal, D, Pomilio, G, Rijal, S, Jabbour, A, Cummins, K, Lackovic, K, Blombery, P, Thompson, E, Ekert, PG, Lessene, G, Glaser, SP, Huang, DCS, Roberts, AW, Guthridge, MA & Wei, AH 2018, 'Enhancing venetoclax activity in acute myeloid leukemia by co-targeting MCL1', Leukemia, vol. 32, no. 2, pp. 303-312. https://doi.org/10.1038/leu.2017.243

Enhancing venetoclax activity in acute myeloid leukemia by co-targeting MCL1. / Teh, T. C.; Nguyen, N. Y.; Moujalled, D. M.; Segal, D.; Pomilio, G.; Rijal, S.; Jabbour, A.; Cummins, K.; Lackovic, K.; Blombery, P.; Thompson, E.; Ekert, P. G.; Lessene, G.; Glaser, S. P.; Huang, D. C.S.; Roberts, A. W.; Guthridge, M. A.; Wei, A. H.

In: Leukemia, Vol. 32, No. 2, 01.02.2018, p. 303-312.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Enhancing venetoclax activity in acute myeloid leukemia by co-targeting MCL1

AU - Teh, T. C.

AU - Nguyen, N. Y.

AU - Moujalled, D. M.

AU - Segal, D.

AU - Pomilio, G.

AU - Rijal, S.

AU - Jabbour, A.

AU - Cummins, K.

AU - Lackovic, K.

AU - Blombery, P.

AU - Thompson, E.

AU - Ekert, P. G.

AU - Lessene, G.

AU - Glaser, S. P.

AU - Huang, D. C.S.

AU - Roberts, A. W.

AU - Guthridge, M. A.

AU - Wei, A. H.

PY - 2018/2/1

Y1 - 2018/2/1

N2 - Targeted therapies are frequently combined with standard cytotoxic drugs to enhance clinical response. Targeting the B-cell lymphoma 2 (BCL-2) family of proteins is an attractive option to combat chemoresistance in leukemia. Preclinical and clinical studies indicate modest single-agent activity with selective BCL-2 inhibitors (for example, venetoclax). We show that venetoclax synergizes with cytarabine and idarubicin to increase antileukemic efficacy in a TP53-dependent manner. Although TP53 deficiency impaired sensitivity to combined venetoclax and chemotherapy, higher-dose idarubicin was able to suppress MCL1 and induce cell death independently of TP53. Consistent with an MCL1-specific effect, cell death from high-dose idarubicin was dependent on proapoptotic Bak. Combining higher-dose idarubicin with venetoclax was able to partially overcome resistance in Bak-deficient cells. Using inducible vectors and venetoclax to differentially target anti-apoptotic BCL-2 family members, BCL-2 and MCL1 emerged as critical and complementary proteins regulating cell survival in acute myeloid leukemia. Dual targeting of BCL-2 and MCL1, but not either alone, prolonged survival of leukemia-bearing mice. In conclusion, our findings support the further investigation of venetoclax in combination with standard chemotherapy, including intensified doses of idarubicin. Venetoclax should also be investigated in combination with direct inhibitors of MCL1 as a chemotherapy-free approach in the future.

AB - Targeted therapies are frequently combined with standard cytotoxic drugs to enhance clinical response. Targeting the B-cell lymphoma 2 (BCL-2) family of proteins is an attractive option to combat chemoresistance in leukemia. Preclinical and clinical studies indicate modest single-agent activity with selective BCL-2 inhibitors (for example, venetoclax). We show that venetoclax synergizes with cytarabine and idarubicin to increase antileukemic efficacy in a TP53-dependent manner. Although TP53 deficiency impaired sensitivity to combined venetoclax and chemotherapy, higher-dose idarubicin was able to suppress MCL1 and induce cell death independently of TP53. Consistent with an MCL1-specific effect, cell death from high-dose idarubicin was dependent on proapoptotic Bak. Combining higher-dose idarubicin with venetoclax was able to partially overcome resistance in Bak-deficient cells. Using inducible vectors and venetoclax to differentially target anti-apoptotic BCL-2 family members, BCL-2 and MCL1 emerged as critical and complementary proteins regulating cell survival in acute myeloid leukemia. Dual targeting of BCL-2 and MCL1, but not either alone, prolonged survival of leukemia-bearing mice. In conclusion, our findings support the further investigation of venetoclax in combination with standard chemotherapy, including intensified doses of idarubicin. Venetoclax should also be investigated in combination with direct inhibitors of MCL1 as a chemotherapy-free approach in the future.

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