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Acute Myeloid Leukemia
Concomitant targeting of BCL2 with venetoclax and MAPK signaling with cobimetinib in acute myeloid leukemia models
Ferrata Storti Foundation
Haematologica 2020 Volume 105(3):697-707
Lina Han,1,2 Qi Zhang,1 Monique Dail,3 Ce Shi,2 Antonio Cavazos,1 Vivian R. Ruvolo,1 Yang Zhao,4 Eugene Kim,3 Mohamed Rahmani,5,6 Duncan H. Mak,1 Sha S. Jin,7 Jun Chen,7 Darren C. Phillips,7 Paul Bottecelli Koller,1 Rodrigo Jacamo,1 Jared K. Burks,1 Courtney DiNardo,1 Naval Daver,1 Elias Jabbour,1 Jing Wang,4 Hagop M. Kantarjian,1 Michael Andreeff,1 Steven Grant,6 Joel D. Leverson,7 Deepak Sampath8 and Marina Konopleva1
1Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 2Department of Hematology, First Affiliated Hospital, Harbin Medical University, Harbin, China; 3Department of Oncology Biomarkers, Genentech, South San Francisco, CA, USA; 4Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 5College of Medicine, Sharjah Institute for Medical Research, University of Sharjah, Sharjah, UAE; 6Division of Hematology/Oncology, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, USA; 7AbbVie Inc., North Chicago, IL, USA and 8Department of Translational Oncology, Genentech, South San Francisco, CA, USA
ABSTRACT
The pathogenesis of acute myeloid leukemia (AML) involves serial acquisition of mutations controlling several cellular processes, requir- ing combination therapies affecting key downstream survival nodes in order to treat the disease effectively. The BCL2 selective inhibitor veneto- clax 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 progen- itors. 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 path- ways 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 com- binatorial blockade of MEK and BCL2 pathways in AML.
Introduction
Acute myeloid leukemia (AML) is characterized by the uncontrolled proliferation and arrested differentiation of abnormal stem and progenitor cells. Standard induction chemotherapy induces a high rate of complete remission but fails to improve overall survival especially in elderly patients with AML.1,2 Genes significantly mutated in AML can be organized into several functional categories that are associated with enhanced proliferation, impaired differentiation, deregulated chromatin modification, and DNA methylation.1,3 Therefore, co-targeting downstream pathways that contribute to
Correspondence:
MARINA KONOPLEVA
mkonople@mdanderson.org
Received: August 28, 2018. Accepted: May 22, 2019. Pre-published: May 23, 2019.
doi:10.3324/haematol.2018.205534
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/105/3/697
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haematologica | 2020; 105(3)
697
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