PCI-32765, BTK Inhibitor

Resume

Small molecule drugs that target the B-cell antigen receptor (BCR) signalosome show clinical efficacy in the treatment of B-cell non-Hodgkin lymphoma. These agents, including Bruton’s tyrosine kinase (BTK) inhibitor PCI -32765, show an unexpected response in patients with chronic lymphocytic leukemia (CLL): a rapid and sustained reduction in lymphadenopathy accompanied by transient lymphocytosis, which is reversible with the temporary withdrawal of the drug. We hypothesize that this clinical response reflects impairment of integrin-mediated adhesion and/or migration.

Here, we show that PCI-32765 strongly inhibits BCR-controlled signaling and α4β1 integrin-mediated adhesion to fibronectin and VCAM-1 of lymphoma cell lines and primary CLL cells. In addition, PCI-32765 also inhibits CXCL12, CXCL13, and CCL19-induced signaling, adhesion, and migration of primary CLL cells. Our data indicate that BTK inhibition by PCI-32765 outpaces BCR- and chemokine-controlled integrin-mediated malignant B cell retention and localization of malignant B cells in their lymph node and bone marrow microenvironment that support growth and survival. , resulting in a clinically evident CLL regression.

Introduction

Chronic lymphocytic leukemia (CLL), the most common adult leukemia, is an incurable malignancy of mature B lymphocytes characterized by the accumulation of resting malignant B cells in peripheral blood and the presence of proliferating malignant B cells in the lymph nodes (LN ), spleen, and bone marrow (MO). It is well established that the tumor microenvironment plays an important role in the pathogenesis of CLL: various cytokines, chemokines, and adhesion molecules provided within the LN, spleen, and BM microenvironment, as well as signaling by the B cell antigen receptor (BCR), they play a fundamental role in the localization, growth, survival and drug resistance of CLL cells.

Because antigen-driven, chronic, or tonic BCR signaling is involved in the pathogenesis of most types of B-cell malignancies, the BCR signalosome provides a rational therapeutic target, even for CLL.9 BTK) is a particularly promising target: it is a key component of the BCR signaling pathway, it is only critical for B cells, and loss of BTK function is not lethal (eg, patients with X-linked agammaglobulinemia and Btk-deficient mice).

Indeed, the irreversible, orally-administered, potent, selective small molecule BTK inhibitor PCI-3276511 shows promising clinical activity in phase 1 and 2 studies in B-cell non-Hodgkin lymphoma, including complete or partial remission in a significant proportion of enrolled patients with diffuse large B-cell lymphoma, mantle cell lymphoma, and CLL.12-14

Interestingly, patients with CLL show an unexpected clinical response to treatment with PCI-32765: a rapid (in days) and sustained reduction of lymphadenopathy is accompanied by transient lymphocytosis, which is reversible after temporary withdrawal of the drug13 (R. Advani, JJB, and N. Fowler, unpublished observations, 2010).

In particular, some of the other effective small molecule drugs that target the BCR signaling pathway, namely the SYK (R788 / R406) and PI3K (CAL-101) inhibitors, show a similar response in clinical trials. with CLL.15,16 On the basis of our previous studies on B17-19 cell adhesion and migration, we hypothesized that this clinical response reflects the attenuated retention of the microenvironment and localization of CLL cells due to adhesion or BCR- or chemokine-controlled integrin-mediated migration.

Methods

Namalwa, Daudi, L363 or primary CLL cells from patients, pretreated for 1 hour with 1μM PCI-32765, were allowed to adhere to 96-well plates coated with fibronectin or VCAM-1 in the presence of anti-IgM, phorbol 12-myristate 13-acetate (PMA), or chemokines (CXCL12, CXCL13, or CCL19), or were allowed to migrate to these chemokines in VCAM-1 coated transwells, essentially as previously described.

For more details and others methods, see Supplementary Methods (available on Blood’s website; see Supplementary Materials link at the top of the online article). This study was carried out and approved by the Medical Committee for Human Experimentation of the Academic Medical Center. Informed consent was obtained in accordance with the Declaration of Helsinki.

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