In vitro, BTK inhibition induces CLL cytotoxicity, decreases NF-κB–dependent transcription, and abrogates chemokine-mediated migration of CLL cells to protective lymphoid microenvironments ( 14, 15). BTK is overexpressed at the transcript and protein level in CLL B cells compared with healthy donors, leading to constitutive BCR activation ( 14). Several pathways that work to increase the survival and proliferation of CLL B cells converge proximally on BTK ( 9) these pathways are initiated at the B-cell receptor (BCR), Toll-like receptors ( 10, 11), and multiple chemokine receptors ( 12, 13), making BTK an attractive therapeutic target. 1, 2) has spurred the development of targeted BTK inhibitors, most notably the irreversible inhibitor ibrutinib ( 3–8). Recent appreciation for the extent to which Bruton tyrosine kinase (BTK) drives select hematologic malignancies such as chronic lymphocytic leukemia (CLL refs. This article is highlighted in the In This Issue feature, p. 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. Significance: This study characterizes a rationally designed kinase inhibitor with efficacy in models recapitulating the most common mechanisms of acquired resistance to ibrutinib.
Additionally, ARQ 531 inhibits CLL cell survival and suppresses BCR-mediated activation of C481S BTK and PLCγ2 mutants, which facilitate clinical resistance to ibrutinib. 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. 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. We hypothesized that targeting additional kinases would improve global inhibition of signaling pathways, producing more robust responses. 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. 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).
0 kommentar(er)
