TY - JOUR
T1 - The btk inhibitor arq 531 targets ibrutinib-resistant cll and richter transformation
AU - Reiff, Sean D.
AU - Mantel, Rose
AU - Smith, Lisa L.
AU - Greene, J. T.
AU - Muhowski, Elizabeth M.
AU - Fabian, Catherine A.
AU - Goettl, Virginia M.
AU - Tran, Minh
AU - Harrington, Bonnie K.
AU - Rogers, Kerry A.
AU - Awan, Farrukh T.
AU - Maddocks, Kami
AU - Andritsos, Leslie
AU - Lehman, Amy M.
AU - Sampath, Deepa
AU - Lapalombella, Rosa
AU - Eathiraj, Sudharshan
AU - Abbadessa, Giovanni
AU - Schwartz, Brian
AU - Johnson, Amy J.
AU - Byrd, John C.
AU - Woyach, Jennifer A.
N1 - Funding Information:
K.A. Rogers is a consultant/advisory board member for Acerta Pharma. F.T. Awan reports receiving a commercial research grant from Pharmacyclics and is a consultant/advisory board member for Pharmacyclics, Gilead, and AbbVie. K. Maddocks is a consultant/advisory board member for Pharmacyclics and AstraZeneca.
Funding Information:
ARQ 531 was provided by ArQule Inc. This research was supported by grants from the NIH (J.A Woyach, K23 CA178183 and R01 CA197870; J.C. Byrd, R35 CA197734 and P30 CA016058).
Publisher Copyright:
©2018 American Association for Cancer Research.
PY - 2018/10
Y1 - 2018/10
N2 - 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-κB gene transcription. In vivo, ARQ 531 was found to increase survival over ibrutinib in a murine Eμ-TCL1 engraftment model of CLL and a murine Eμ-MYC/ TCL1 engraftment model resembling Richter transformation. Additionally, ARQ 531 inhibits CLL cell survival and suppresses BCR-mediated activation of C481S BTK and PLCγ2 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.
AB - 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-κB gene transcription. In vivo, ARQ 531 was found to increase survival over ibrutinib in a murine Eμ-TCL1 engraftment model of CLL and a murine Eμ-MYC/ TCL1 engraftment model resembling Richter transformation. Additionally, ARQ 531 inhibits CLL cell survival and suppresses BCR-mediated activation of C481S BTK and PLCγ2 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.
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U2 - 10.1158/2159-8290.CD-17-1409
DO - 10.1158/2159-8290.CD-17-1409
M3 - Article
C2 - 30093506
AN - SCOPUS:85054419893
SN - 2159-8274
VL - 8
SP - 1300
EP - 1315
JO - Cancer discovery
JF - Cancer discovery
IS - 10
ER -