Combining BH3-Mimetics to target both BCL-2 and MCL1 has potent activity in pre-clinical models of acute myeloid leukemia

Donia M. Moujalled, Giovanna Pomilio, Corina Ghiurau, Adam Ivey, Jessica Salmon, Sewa Rijal, Sarah Macraild, Lan Zhang, Tse Chieh Teh, Ing Soo Tiong, Ping Lan, Maia Chanrion, Audrey Claperon, Francesca Rocchetti, Adrien Zichi, Laurence Kraus-Berthier, Youzhen Wang, Ensar Halilovic, Erick Morris, Frédéric Colland & 7 others David Segal, David Huang, Andrew W. Roberts, Ana Leticia Maragno, Guillaume Lessene, Olivier Geneste, Andrew H. Wei

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Improving outcomes in acute myeloid leukemia (AML) remains a major clinical challenge. Overexpression of pro-survival BCL-2 family members rendering transformed cells resistant to cytotoxic drugs is a common theme in cancer. Targeting BCL-2 with the BH3-mimetic venetoclax is active in AML when combined with low-dose chemotherapy or hypomethylating agents. We now report the pre-clinical anti-leukemic efficacy of a novel BCL-2 inhibitor S55746, which demonstrates synergistic pro-apoptotic activity in combination with the MCL1 inhibitor S63845. Activity of the combination was caspase and BAX/BAK dependent, superior to combination with standard cytotoxic AML drugs and active against a broad spectrum of poor risk genotypes, including primary samples from patients with chemoresistant AML. Co-targeting BCL-2 and MCL1 was more effective against leukemic, compared to normal hematopoietic progenitors, suggesting a therapeutic window of activity. Finally, S55746 combined with S63845 prolonged survival in xenograft models of AML and suppressed patient-derived leukemia but not normal hematopoietic cells in bone marrow of engrafted mice. In conclusion, a dual BH3-mimetic approach is feasible, highly synergistic, and active in diverse models of human AML. This approach has strong clinical potential to rapidly suppress leukemia, with reduced toxicity to normal hematopoietic precursors compared to chemotherapy.

Original languageEnglish
Pages (from-to)905-917
Number of pages13
JournalLeukemia
Volume33
Issue numbera
DOIs
Publication statusPublished - 1 Apr 2019

Cite this

Moujalled, Donia M. ; Pomilio, Giovanna ; Ghiurau, Corina ; Ivey, Adam ; Salmon, Jessica ; Rijal, Sewa ; Macraild, Sarah ; Zhang, Lan ; Teh, Tse Chieh ; Tiong, Ing Soo ; Lan, Ping ; Chanrion, Maia ; Claperon, Audrey ; Rocchetti, Francesca ; Zichi, Adrien ; Kraus-Berthier, Laurence ; Wang, Youzhen ; Halilovic, Ensar ; Morris, Erick ; Colland, Frédéric ; Segal, David ; Huang, David ; Roberts, Andrew W. ; Maragno, Ana Leticia ; Lessene, Guillaume ; Geneste, Olivier ; Wei, Andrew H. / Combining BH3-Mimetics to target both BCL-2 and MCL1 has potent activity in pre-clinical models of acute myeloid leukemia. In: Leukemia. 2019 ; Vol. 33, No. a. pp. 905-917.
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title = "Combining BH3-Mimetics to target both BCL-2 and MCL1 has potent activity in pre-clinical models of acute myeloid leukemia",
abstract = "Improving outcomes in acute myeloid leukemia (AML) remains a major clinical challenge. Overexpression of pro-survival BCL-2 family members rendering transformed cells resistant to cytotoxic drugs is a common theme in cancer. Targeting BCL-2 with the BH3-mimetic venetoclax is active in AML when combined with low-dose chemotherapy or hypomethylating agents. We now report the pre-clinical anti-leukemic efficacy of a novel BCL-2 inhibitor S55746, which demonstrates synergistic pro-apoptotic activity in combination with the MCL1 inhibitor S63845. Activity of the combination was caspase and BAX/BAK dependent, superior to combination with standard cytotoxic AML drugs and active against a broad spectrum of poor risk genotypes, including primary samples from patients with chemoresistant AML. Co-targeting BCL-2 and MCL1 was more effective against leukemic, compared to normal hematopoietic progenitors, suggesting a therapeutic window of activity. Finally, S55746 combined with S63845 prolonged survival in xenograft models of AML and suppressed patient-derived leukemia but not normal hematopoietic cells in bone marrow of engrafted mice. In conclusion, a dual BH3-mimetic approach is feasible, highly synergistic, and active in diverse models of human AML. This approach has strong clinical potential to rapidly suppress leukemia, with reduced toxicity to normal hematopoietic precursors compared to chemotherapy.",
author = "Moujalled, {Donia M.} and Giovanna Pomilio and Corina Ghiurau and Adam Ivey and Jessica Salmon and Sewa Rijal and Sarah Macraild and Lan Zhang and Teh, {Tse Chieh} and Tiong, {Ing Soo} and Ping Lan and Maia Chanrion and Audrey Claperon and Francesca Rocchetti and Adrien Zichi and Laurence Kraus-Berthier and Youzhen Wang and Ensar Halilovic and Erick Morris and Fr{\'e}d{\'e}ric Colland and David Segal and David Huang and Roberts, {Andrew W.} and Maragno, {Ana Leticia} and Guillaume Lessene and Olivier Geneste and Wei, {Andrew H.}",
year = "2019",
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doi = "10.1038/s41375-018-0261-3",
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Moujalled, DM, Pomilio, G, Ghiurau, C, Ivey, A, Salmon, J, Rijal, S, Macraild, S, Zhang, L, Teh, TC, Tiong, IS, Lan, P, Chanrion, M, Claperon, A, Rocchetti, F, Zichi, A, Kraus-Berthier, L, Wang, Y, Halilovic, E, Morris, E, Colland, F, Segal, D, Huang, D, Roberts, AW, Maragno, AL, Lessene, G, Geneste, O & Wei, AH 2019, 'Combining BH3-Mimetics to target both BCL-2 and MCL1 has potent activity in pre-clinical models of acute myeloid leukemia' Leukemia, vol. 33, no. a, pp. 905-917. https://doi.org/10.1038/s41375-018-0261-3

Combining BH3-Mimetics to target both BCL-2 and MCL1 has potent activity in pre-clinical models of acute myeloid leukemia. / Moujalled, Donia M.; Pomilio, Giovanna; Ghiurau, Corina; Ivey, Adam; Salmon, Jessica; Rijal, Sewa; Macraild, Sarah; Zhang, Lan; Teh, Tse Chieh; Tiong, Ing Soo; Lan, Ping; Chanrion, Maia; Claperon, Audrey; Rocchetti, Francesca; Zichi, Adrien; Kraus-Berthier, Laurence; Wang, Youzhen; Halilovic, Ensar; Morris, Erick; Colland, Frédéric; Segal, David; Huang, David; Roberts, Andrew W.; Maragno, Ana Leticia; Lessene, Guillaume; Geneste, Olivier; Wei, Andrew H.

In: Leukemia, Vol. 33, No. a, 01.04.2019, p. 905-917.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Combining BH3-Mimetics to target both BCL-2 and MCL1 has potent activity in pre-clinical models of acute myeloid leukemia

AU - Moujalled, Donia M.

AU - Pomilio, Giovanna

AU - Ghiurau, Corina

AU - Ivey, Adam

AU - Salmon, Jessica

AU - Rijal, Sewa

AU - Macraild, Sarah

AU - Zhang, Lan

AU - Teh, Tse Chieh

AU - Tiong, Ing Soo

AU - Lan, Ping

AU - Chanrion, Maia

AU - Claperon, Audrey

AU - Rocchetti, Francesca

AU - Zichi, Adrien

AU - Kraus-Berthier, Laurence

AU - Wang, Youzhen

AU - Halilovic, Ensar

AU - Morris, Erick

AU - Colland, Frédéric

AU - Segal, David

AU - Huang, David

AU - Roberts, Andrew W.

AU - Maragno, Ana Leticia

AU - Lessene, Guillaume

AU - Geneste, Olivier

AU - Wei, Andrew H.

PY - 2019/4/1

Y1 - 2019/4/1

N2 - Improving outcomes in acute myeloid leukemia (AML) remains a major clinical challenge. Overexpression of pro-survival BCL-2 family members rendering transformed cells resistant to cytotoxic drugs is a common theme in cancer. Targeting BCL-2 with the BH3-mimetic venetoclax is active in AML when combined with low-dose chemotherapy or hypomethylating agents. We now report the pre-clinical anti-leukemic efficacy of a novel BCL-2 inhibitor S55746, which demonstrates synergistic pro-apoptotic activity in combination with the MCL1 inhibitor S63845. Activity of the combination was caspase and BAX/BAK dependent, superior to combination with standard cytotoxic AML drugs and active against a broad spectrum of poor risk genotypes, including primary samples from patients with chemoresistant AML. Co-targeting BCL-2 and MCL1 was more effective against leukemic, compared to normal hematopoietic progenitors, suggesting a therapeutic window of activity. Finally, S55746 combined with S63845 prolonged survival in xenograft models of AML and suppressed patient-derived leukemia but not normal hematopoietic cells in bone marrow of engrafted mice. In conclusion, a dual BH3-mimetic approach is feasible, highly synergistic, and active in diverse models of human AML. This approach has strong clinical potential to rapidly suppress leukemia, with reduced toxicity to normal hematopoietic precursors compared to chemotherapy.

AB - Improving outcomes in acute myeloid leukemia (AML) remains a major clinical challenge. Overexpression of pro-survival BCL-2 family members rendering transformed cells resistant to cytotoxic drugs is a common theme in cancer. Targeting BCL-2 with the BH3-mimetic venetoclax is active in AML when combined with low-dose chemotherapy or hypomethylating agents. We now report the pre-clinical anti-leukemic efficacy of a novel BCL-2 inhibitor S55746, which demonstrates synergistic pro-apoptotic activity in combination with the MCL1 inhibitor S63845. Activity of the combination was caspase and BAX/BAK dependent, superior to combination with standard cytotoxic AML drugs and active against a broad spectrum of poor risk genotypes, including primary samples from patients with chemoresistant AML. Co-targeting BCL-2 and MCL1 was more effective against leukemic, compared to normal hematopoietic progenitors, suggesting a therapeutic window of activity. Finally, S55746 combined with S63845 prolonged survival in xenograft models of AML and suppressed patient-derived leukemia but not normal hematopoietic cells in bone marrow of engrafted mice. In conclusion, a dual BH3-mimetic approach is feasible, highly synergistic, and active in diverse models of human AML. This approach has strong clinical potential to rapidly suppress leukemia, with reduced toxicity to normal hematopoietic precursors compared to chemotherapy.

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U2 - 10.1038/s41375-018-0261-3

DO - 10.1038/s41375-018-0261-3

M3 - Article

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SP - 905

EP - 917

JO - Leukemia

JF - Leukemia

SN - 0887-6924

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