Superior efficacy of cotreatment with BET protein inhibitor and BCL2 or MCL1 inhibitor against AML blast progenitor cells
Year: 2019
Type: article
Abstract: First-generation bromodomain extra-terminal protein (BETP) inhibitors (BETi) (e.g., OTX015) that disrupt binding of BETP BRD4 to chromatin transcriptionally attenuate AML-relevant progrowth and prosurvival oncoproteins. BETi treatment induces apoptosis of AML BPCs, reduces in vivo AML burden and induces clinical remissions in a minority of AML patients. Clinical efficacy of more potent BETis, e.g., ABBV-075 (AbbVie, Inc.), is being evaluated. Venetoclax and A-1210477 bind and inhibit the antiapoptotic activity of BCL2 and MCL1, respectively, lowering the threshold for apoptosis. BETi treatment is shown here to perturb accessible chromatin and activity of enhancers/promoters, attenuating MYC, CDK6, MCL1 and BCL2, while inducing BIM, HEXIM1, CDKN1A expressions and apoptosis of AML cells. Treatment with venetoclax increased MCL1 protein levels, but cotreatment with ABBV-075 reduced MCL1 and Bcl-xL levels. ABBV-075 cotreatment synergistically induced apoptosis with venetoclax or A-1210477 in patient-derived, CD34+ AML cells. Compared to treatment with either agent alone, cotreatment with ABBV-075 and venetoclax was significantly more effective in reducing AML cell-burden and improving survival, without inducing toxicity, in AML-engrafted immune-depleted mice. These findings highlight the basis of superior activity and support interrogation of clinical efficacy and safety of cotreatment with BETi and BCL2 or MCL1 inhibitor in AML.
Source: Blood Cancer Journal
Authors: Warren Fiskus, Tianyu Cai, Courtney D. DiNardo, Steven M. Kornblau, Gautam Borthakur, Tapan M. Kadia, Naveen Pemmaraju, Prithviraj Bose, Lucia Masarova, Kimal Rajapakshe, Dimuthu Perera, Cristian Coarfa, Christopher P. Mill, Dyana T. Saenz, David N. Saenz, Baohua Sun, Joseph D. Khoury, Yu Shen, Marina Konopleva, Kapil N. Bhalla
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $4,380
Funders: Michael and Susan Dell Foundation, Mary K. Chapman Foundation, SRA International, Cancer Prevention and Research Institute of Texas, Dan L. Duncan Cancer Center, Baylor College of Medicine, National Institutes of Health, University of Texas MD Anderson Cancer Center, National Cancer Institute
Awards: G111615301, Developing Effective Epigenetic Biomarkers to Identify Individuals with High Risk of Cancer, G1468253849, G1901027039, G2169464185, G2659503640, G281858550, G286749731, G293715275, G2947552126, G299588672, G3746653997, G418187648, G4195384610, G4276892241, Proteomics and Metabolomics Core Facility, G5465708471, Targeted Therapy for AML Stem Cells, G5508324684, Integrative Pipeline for Analysis & Translational Application of TCGA Data (GDAC), G6526681941, G6736661663, G7557813972, G7837447426, G788993117, G8271546232, The University of Texas M. D. Anderson Cancer Center SPORE in Ovarian Cancer, G8817362204, G9000034222, G9000038294, G9000041527, G9000079746, G9000223477, G9000240210, Baylor College of Medicine Cancer Center - Cancer Center Support Grant
OpenAlex ID: W2909486746