Concomitant targeting of BCL2 with venetoclax and MAPK signaling with cobimetinib in acute myeloid leukemia models
Lina Han,
Qi Zhang,
Monique Dail,
Ce Shi,
Antonio Cavazos,
Vivian R. Ruvolo,
Yang Zhao,
Eugene Kim,
Mohamed Rahmani,
Duncan H. Mak,
Sha S. Jin,
Jun Chen,
Darren C. Phillips,
Paul Bottecelli Koller,
Rodrigo Jacamo,
Jared K. Burks,
Courtney DiNardo,
Naval Daver,
Elias Jabbour,
Jing Wang,
Hagop M. Kantarjian,
Michael Andreeff,
Steven Grant,
Joel D. Leverson,
Deepak Sampath,
Marina Konopleva
Affiliations
Lina Han
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
Qi Zhang
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Monique Dail
Department of Oncology Biomarkers, Genentech, South San Francisco, CA, USA
Ce Shi
Department of Hematology, First Affiliated Hospital, Harbin Medical University, Harbin, China
Antonio Cavazos
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Vivian R. Ruvolo
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Yang Zhao
Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Eugene Kim
Department of Oncology Biomarkers, Genentech, South San Francisco, CA, USA
Mohamed Rahmani
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
Duncan H. Mak
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Sha S. Jin
AbbVie Inc., North Chicago, IL, USA
Jun Chen
AbbVie Inc., North Chicago, IL, USA
Darren C. Phillips
AbbVie Inc., North Chicago, IL, USA
Paul Bottecelli Koller
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Rodrigo Jacamo
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Jared K. Burks
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Courtney DiNardo
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Naval Daver
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Elias Jabbour
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Jing Wang
Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Hagop M. Kantarjian
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Michael Andreeff
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Steven Grant
Division of Hematology/Oncology, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, USA
Joel D. Leverson
AbbVie Inc., North Chicago, IL, USA
Deepak Sampath
Department of Translational Oncology, Genentech, South San Francisco, CA, USA
Marina Konopleva
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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.
