Concomitant targeting of BCL2 with venetoclax and MAPK signaling with cobimetinib in acute myeloid leukemia models.

Autor:	Han L; Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.; Department of Hematology, First Affiliated Hospital, Harbin Medical University, Harbin, China., Zhang Q; Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Dail M; Department of Oncology Biomarkers, Genentech, South San Francisco, CA, USA., Shi C; Department of Hematology, First Affiliated Hospital, Harbin Medical University, Harbin, China., Cavazos A; Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Ruvolo VR; Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Zhao Y; Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Kim E; Department of Oncology Biomarkers, Genentech, South San Francisco, CA, USA., Rahmani M; College of Medicine, Sharjah Institute for Medical Research, University of Sharjah, Sharjah, UAE.; Division of Hematology/Oncology, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, USA., Mak DH; Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Jin SS; AbbVie Inc., North Chicago, IL, USA., Chen J; AbbVie Inc., North Chicago, IL, USA., Phillips DC; AbbVie Inc., North Chicago, IL, USA., Koller PB; Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Jacamo R; Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Burks JK; Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., DiNardo C; Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Daver N; Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Jabbour E; Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Wang J; Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Kantarjian HM; Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Andreeff M; Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Grant S; Division of Hematology/Oncology, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, USA., Leverson JD; AbbVie Inc., North Chicago, IL, USA., Sampath D; Department of Translational Oncology, Genentech, South San Francisco, CA, USA., Konopleva M; Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA mkonople@mdanderson.org.
Jazyk:	angličtina
Zdroj:	Haematologica [Haematologica] 2020 Mar; Vol. 105 (3), pp. 697-707. Date of Electronic Publication: 2019 May 23.
DOI:	10.3324/haematol.2018.205534
Abstrakt:	The pathogenesis of acute myeloid leukemia (AML) involves serial acquisition of mutations controlling several cellular processes, requiring combination therapies affecting key downstream survival nodes in order to treat the disease effectively. The BCL2 selective inhibitor venetoclax has potent anti-leukemia efficacy; however, resistance can occur due to its inability to inhibit MCL1, which is stabilized by the MAPK pathway. In this study, we aimed to determine the anti-leukemia efficacy of concomitant targeting of the BCL2 and MAPK pathways by venetoclax and the MEK1/2 inhibitor cobimetinib, respectively. The combination demonstrated synergy in seven of 11 AML cell lines, including those resistant to single agents, and showed growth-inhibitory activity in over 60% of primary samples from patients with diverse genetic alterations. The combination markedly impaired leukemia progenitor functions, while maintaining normal progenitors. Mass cytometry data revealed that BCL2 protein is enriched in leukemia stem/progenitor cells, primarily in venetoclax-sensitive samples, and that cobimetinib suppressed cytokine-induced pERK and pS6 signaling pathways. Through proteomic profiling studies, we identified several pathways inhibited downstream of MAPK that contribute to the synergy of the combination. In OCI-AML3 cells, the combination downregulated MCL1 protein levels and disrupted both BCL2:BIM and MCL1:BIM complexes, releasing BIM to induce cell death. RNA sequencing identified several enriched pathways, including MYC, mTORC1, and p53 in cells sensitive to the drug combination. In vivo , the venetoclax-cobimetinib combination reduced leukemia burden in xenograft models using genetically engineered OCI-AML3 and MOLM13 cells. Our data thus provide a rationale for combinatorial blockade of MEK and BCL2 pathways in AML. (Copyright© 2020 Ferrata Storti Foundation.)
Databáze:	MEDLINE
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