Superior efficacy of cotreatment with BET protein inhibitor and BCL2 or MCL1 inhibitor against AML blast progenitor cells

• Published in: Blood cancer journal (New York) 2019-01, Vol.9 (2), p.4, Article 4
• Main Authors: Fiskus, Warren, Cai, Tianyu, DiNardo, Courtney D., Kornblau, Steven M., Borthakur, Gautam, Kadia, Tapan M., Pemmaraju, Naveen, Bose, Prithviraj, Masarova, Lucia, Rajapakshe, Kimal, Perera, Dimuthu, Coarfa, Cristian, Mill, Christopher P., Saenz, Dyana T., Saenz, David N., Sun, Baohua, Khoury, Joseph D., Shen, Yu, Konopleva, Marina, Bhalla, Kapil N.
• Format: Article
• Language: English
• Subjects: 13/106; 13/2; 13/31; 38; 38/90; 38/91; 59; 59/5; 631/67/1059/602; 64; 64/60; 692/699/1541/1990/283/1897; 82; 82/1; Animals; Antineoplastic Agents - pharmacology; Apoptosis; Binding Sites; Biomarkers, Tumor; Biomedical and Life Sciences; Biomedicine; Cancer Research; Cell Line, Tumor; Disease Models, Animal; Drug Synergism; Female; Hematology; Humans; Indoles - pharmacology; Leukemia, Myeloid, Acute - drug therapy; Leukemia, Myeloid, Acute - metabolism; Leukemia, Myeloid, Acute - mortality; Leukemia, Myeloid, Acute - pathology; Myeloid Cell Leukemia Sequence 1 Protein - antagonists & inhibitors; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - metabolism; Oncology; Protein Binding; Protein Kinase Inhibitors - pharmacology; Proteins; Proteins - antagonists & inhibitors; Proto-Oncogene Proteins c-bcl-2 - antagonists & inhibitors; Pyridones - pharmacology; Sulfonamides - pharmacology; Xenograft Model Antitumor Assays
• ISSN: 2044-5385; 2044-5385
• DOI: 10.1038/s41408-018-0165-5

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.