The BTK Inhibitor ARQ 531 Targets Ibrutinib-Resistant CLL and Richter Transformation

被引:133
作者
Reiff, Sean D. [1 ,2 ]
Mantel, Rose [1 ]
Smith, Lisa L. [1 ]
Greene, J. T. [1 ]
Muhowski, Elizabeth M. [3 ]
Fabian, Catherine A. [1 ]
Goettl, Virginia M. [1 ]
Tran, Minh [1 ]
Harrington, Bonnie K. [1 ]
Rogers, Kerry A. [1 ]
Awan, Farrukh T. [1 ]
Maddocks, Kami [1 ]
Andritsos, Leslie [1 ]
Lehman, Amy M. [4 ]
Sampath, Deepa [1 ]
Lapalombella, Rosa [1 ]
Eathiraj, Sudharshan [5 ]
Abbadessa, Giovanni [5 ,6 ]
Schwart, Brian [5 ]
Johnson, Amy J. [1 ,3 ,7 ]
Byrd, John C. [1 ,3 ]
Woyach, Jennifer A. [1 ,3 ]
机构
[1] Ohio State Univ, Ctr Comprehens Canc, Div Hematol, Dept Internal Med, Columbus, OH 43210 USA
[2] Ohio State Univ, Med Scientist Training Program, Columbus, OH 43210 USA
[3] Ohio State Univ, Coll Pharm, Div Pharmaceut, 500 W 12Th Ave, Columbus, OH 43210 USA
[4] Ohio State Univ, Ctr Biostat, Columbus, OH 43210 USA
[5] ArQule, One Wall St, Burlington, MA USA
[6] Sanofi Genzyme, Cambridge, MA USA
[7] Janssen Res & Dev, Beerse, Belgium
关键词
CHRONIC LYMPHOCYTIC-LEUKEMIA; B-CELL RECEPTOR; BRUTONS TYROSINE KINASE; THERAPEUTIC TARGET; MUTATIONS; PCI-32765; PROLIFERATION; ACTIVATION; SYNERGIZES; APOPTOSIS;
D O I
10.1158/2159-8290.CD-17-1409
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Targeted inhibition of Bruton tyrosine kinase (BTK) with the irreversible inhibitor ibrutinib has improved outcomes for patients with hematologic malignancies, including chronic lymphocytic leukemia (CLL). Here, we describe preclinical investigations of ARQ 531, a potent, reversible inhibitor of BTK with additional activity against Src family kinases and kinases related to ERK signaling. We hypothesized that targeting additional kinases would improve global inhibition of signaling pathways, producing more robust responses. In vitro treatment of patient CLL cells with ARQ 531 decreases BTK-mediated functions including B-cell receptor (BCR) signaling, viability, migration, CD40 and CD86 expression, and NF-KB gene transcription. In vivo, ARQ 531 was found to increase survival over ibrutinib in a murine ER-TCL1 engraftment model of CLL and a murine EA-MYC/ TCL1 engraftment model resembling Richter transformation. Additionally, ARQ 531 inhibits CLL cell survival and suppresses BCR-mediated activation of C481S BTK and PLCy2 mutants, which facilitate clinical resistance to ibrutinib. SIGNIFICANCE: This study characterizes a rationally designed kinase inhibitor with efficacy in models recapitulating the most common mechanisms of acquired resistance to ibrutinib. Reversible BTK inhibition is a promising strategy to combat progressive CLL, and multikinase inhibition demonstrates superior efficacy to targeted ibrutinib therapy in the setting of Richter transformation. (C) 2018 AACR.
引用
收藏
页码:1300 / 1315
页数:16
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