title: Pharmacological and Protein Profiling Suggests Venetoclax (ABT-199) as Optimal Partner with Ibrutinib in Chronic Lymphocytic Leukemia.
abstract: OBJECTIVE
  Bruton's tyrosine kinase (BTK) is a critical enzyme in the B-cell receptor pathway and is inhibited by ibrutinib due to covalent binding to the kinase domain. Though ibrutinib results in impressive clinical activity in chronic lymphocytic leukemia (CLL), most patients achieve only partial remission due to residual disease. We performed a pharmacologic profiling of residual circulating CLL cells from patients receiving ibrutinib to identify optimal agents that could induce cell death of these lymphocytes.
  
  
  METHODS
  Ex vivo serial samples of CLL cells from patients on ibrutinib were obtained prior and after (weeks 2, 4, and 12) the start of treatment. These cells were incubated with PI3K inhibitors (idelalisib or IPI-145), bendamustine, additional ibrutinib, or BCL-2 antagonists (ABT-737 or ABT-199), and cell death was measured. In vitro investigations complemented ex vivo studies. Immunoblots for BTK signaling pathway and antiapoptotic proteins were performed.
  
  
  RESULTS
  The BCL-2 antagonists, especially ABT-199, induced high cell death during ex vivo incubations. In concert with the ex vivo data, in vitro combinations also resulted in high cytotoxicity. Serial samples of CLL cells obtained before and 2, 4, 12, or 36 weeks after the start of ibrutinib showed inhibition of BTK activity and sensitivity to ABTs. Among the three BCL-2 family antiapoptotic proteins that are overexpressed in CLL, levels of MCL-1 and BCL-XL were decreased after ibrutinib while ABT-199 selectively antagonizes BCL-2.
  
  
  CONCLUSIONS
  Our biologic and molecular results suggest that ibrutinib and ABT-199 combination should be tested clinically against CLL.
authors.affiliation: Department of Experimental Therapeutics, MD Anderson Cancer Center, Houston, Texas.
authors.forename: Fabiola
authors.initials: F
authors.lastname: Cervantes-Gomez
authors.affiliation: Department of Experimental Therapeutics, MD Anderson Cancer Center, Houston, Texas.
authors.forename: Betty
authors.initials: B
authors.lastname: Lamothe
authors.affiliation: Division of Hematology, The Ohio State University, Columbus, Ohio.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Woyach
authors.affiliation: Department of Leukemia, MD Anderson Cancer Center, Houston, Texas.
authors.forename: William G
authors.initials: WG
authors.lastname: Wierda
authors.affiliation: Department of Leukemia, MD Anderson Cancer Center, Houston, Texas.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Keating
authors.affiliation: Department of Experimental Therapeutics, MD Anderson Cancer Center, Houston, Texas.
authors.forename: Kumudha
authors.initials: K
authors.lastname: Balakrishnan
authors.affiliation: Department of Experimental Therapeutics, MD Anderson Cancer Center, Houston, Texas. Department of Leukemia, MD Anderson Cancer Center, Houston, Texas. vgandhi@mdanderson.org.
authors.forename: Varsha
authors.initials: V
authors.lastname: Gandhi
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects; D053264:B-Cell Activating Factor / Q000096:biosynthesis / Q000235:genetics; D000069461:Bendamustine Hydrochloride / Q000008:administration & dosage; D001713:Biphenyl Compounds / Q000008:administration & dosage; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000008:administration & dosage*; D005260:Female; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006801:Humans; D007546:Isoquinolines / Q000008:administration & dosage; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008297:Male; D009360:Neoplastic Cells, Circulating / Q000187:drug effects / Q000378:metabolism; D009596:Nitrophenols / Q000008:administration & dosage; D010879:Piperazines / Q000008:administration & dosage; D010880:Piperidines; D011505:Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D011687:Purines / Q000008:administration & dosage; D011720:Pyrazoles / Q000008:administration & dosage*; D011743:Pyrimidines / Q000008:administration & dosage*; D013449:Sulfonamides / Q000008:administration & dosage*; D051020:bcl-X Protein / Q000096:biosynthesis
chemical_list: C501332:ABT-737; D053264:B-Cell Activating Factor; C494811:BCL2L1 protein, human; D001713:Biphenyl Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D007546:Isoquinolines; D009596:Nitrophenols; D010879:Piperazines; D010880:Piperidines; D019253:Proto-Oncogene Proteins c-bcl-2; D011687:Purines; D011720:Pyrazoles; D011743:Pyrimidines; D013449:Sulfonamides; D051020:bcl-X Protein; C551803:ibrutinib; C586691:duvelisib; D000069461:Bendamustine Hydrochloride; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; D000225:Adenine; C579720:venetoclax
references.citation: Blood. 2014 Mar 20;123(12):1810-7
references.pmid: 24415539
references.citation: Lancet Oncol. 2014 Sep;15(10):1090-9
references.pmid: 25150798
references.citation: Blood. 2005 Jun 15;105(12):4820-7
references.pmid: 15728130
references.citation: Blood. 2008 Aug 15;112(4):975-80
references.pmid: 18411418
references.citation: Nat Med. 2013 Feb;19(2):202-8
references.pmid: 23291630
references.citation: Nat Rev Cancer. 2010 Jan;10(1):37-50
references.pmid: 19956173
references.citation: Neoplasia. 2014 Dec;16(12):1036-46
references.pmid: 25499217
references.citation: Blood. 2006 Feb 15;107(4):1276-83
references.pmid: 16204307
references.citation: J Clin Invest. 2007 Jan;117(1):112-21
references.pmid: 17200714
references.citation: Blood. 2011 Jan 13;117(2):563-74
references.pmid: 20940416
references.citation: Blood. 2015 Jan 8;125(2):407-10
references.pmid: 25573971
references.citation: Clin Cancer Res. 2009 Dec 15;15(24):7456-7461
references.pmid: 19996200
references.citation: Proc Natl Acad Sci U S A. 2013 Apr 16;110(16):E1500-7
references.pmid: 23550156
references.citation: Curr Opin Oncol. 2012 Nov;24(6):643-9
references.pmid: 22960555
references.citation: N Engl J Med. 2005 Feb 24;352(8):804-15
references.pmid: 15728813
references.citation: Blood. 2014 Nov 13;124(20):3059-64
references.pmid: 25281606
references.citation: Proc Natl Acad Sci U S A. 2010 Jul 20;107(29):13075-80
references.pmid: 20615965
references.citation: N Engl J Med. 2013 Jul 4;369(1):32-42
references.pmid: 23782158
references.citation: Blood. 2012 Feb 2;119(5):1182-9
references.pmid: 22180443
references.citation: Lancet Oncol. 2015 Feb;16(2):169-76
references.pmid: 25555420
references.citation: Proc Natl Acad Sci U S A. 2014 Feb 11;111(6):2349-54
references.pmid: 24469833
references.citation: ChemMedChem. 2007 Jan;2(1):58-61
references.pmid: 17154430
references.citation: Blood. 2014 May 22;123(21):3247-54
references.pmid: 24652989
references.citation: J Clin Oncol. 2013 Jan 1;31(1):88-94
references.pmid: 23045577
references.citation: Br J Haematol. 2015 Jul;170(1):134-8
references.pmid: 25582069
references.citation: Lancet Oncol. 2014 Jan;15(1):48-58
references.pmid: 24332241
references.citation: Leukemia. 2015 Apr;29(4):895-900
references.pmid: 25189416
references.citation: Blood. 2008 Jan 15;111(2):846-55
references.pmid: 17928528
references.citation: J Clin Oncol. 2005 Jun 20;23(18):4070-8
references.pmid: 15767647
references.citation: Invest New Drugs. 2013 Oct;31(5):1384-94
references.pmid: 23907405
references.citation: Curr Hematol Malig Rep. 2012 Mar;7(1):26-33
references.pmid: 22105489
references.citation: Chem Biol. 2013 Nov 21;20(11):1364-74
references.pmid: 24211136
references.citation: Blood. 2010 Sep 23;116(12):2078-88
references.pmid: 20522708
references.citation: J Clin Oncol. 2012 Feb 10;30(5):488-96
references.pmid: 22184378
references.citation: Blood. 2009 Oct 15;114(16):3382-91
references.pmid: 19605849
references.citation: Br J Haematol. 2015 Mar;168(5):765-8
references.pmid: 25284608
references.citation: Leukemia. 2014 Mar;28(3):649-57
references.pmid: 24270740
references.citation: Blood. 2014 May 22;123(21):3286-95
references.pmid: 24659631
references.citation: Blood. 2012 Mar 15;119(11):2590-4
references.pmid: 22279054
references.citation: Blood. 2009 Mar 26;113(13):3050-8
references.pmid: 19074730
references.citation: Br J Haematol. 2012 Jul;158(2):216-31
references.pmid: 22571278
references.citation: Blood. 2011 Jun 9;117(23):6287-96
references.pmid: 21422473
references.citation: N Engl J Med. 2014 Jun 12;370(24):2286-94
references.pmid: 24869598
references.citation: Blood Cancer J. 2013 Sep 20;3:e149
references.pmid: 24056719
references.citation: Nature. 2005 Jun 2;435(7042):677-81
references.pmid: 15902208
references.citation: Cell Death Dis. 2015;6:e1593
references.pmid: 25590803