The clinically active BTK inhibitor PCI-32765 targets B-cell receptor– and chemokine-controlled adhesion and migration in chronic lymphocytic leukemia

Abstract

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 the Bruton tyrosine kinase (BTK) inhibitor PCI-32765, display an unexpected response in patients with chronic lymphocytic leukemia (CLL): a rapid and sustained reduction of lymphadenopathy accompanied by transient lymphocytosis, which is reversible upon temporary drug deprivation. We hypothesized that this clinical response reflects impaired integrin-mediated adhesion and/or migration. Here, we show that PCI-32765 strongly inhibits BCR-controlled signaling and integrin α(4)β(1)-mediated adhesion to fibronectin and VCAM-1 of lymphoma cell lines and primary CLL cells. Furthermore, PCI-32765 also inhibits CXCL12-, CXCL13-, and CCL19-induced signaling, adhesion, and migration of primary CLL cells. Our data indicate that inhibition of BTK by PCI-32765 overcomes BCR- and chemokine-controlled integrin-mediated retention and homing of malignant B cells in their growth- and survival-supporting lymph node and bone marrow microenvironment, which results in clinically evident CLL regression.

Chronic lymphocytic leukemia: Time to go past genomics?

“…In addition, prominent intracellular signaling is observed in CLL cells from or egressing from lymph node, suggesting that lymph nodes are sites of survival and proliferative stimulus [72]. As a consequence, ibrutinib treatment, which inhibits BCR signaling, leads to a transient increase in circulating CLL cells concurrent with the reduction in lymphadenopathy [75][76][77].…”

Safety and activity of BTK inhibitor ibrutinib combined with ofatumumab in chronic lymphocytic leukemia: a phase 1b/2 study

“…In preclinical models, ibrutinib induced apoptosis and decreased survival of CLL cells and inhibited their homing, migration, and adhesion to the tumor microenvironment. [18][19][20] Recently, in the phase 3 RESONATE trial (PCYC-1112-CA) in relapsed/refractory CLL, ibrutinib demonstrated a statistically significant 78% reduction in the risk of progression or death and a 56% reduction in the risk of death compared with ofatumumab. 21 Ibrutinib was US Food and Drug Administration-approved for treatment of patients with CLL who received $1 prior therapy and for patients with CLL with del (17)(p13.1).…”

Evolution of ibrutinib resistance in chronic lymphocytic leukemia (CLL)

“…Preclinical models demonstrated that ibrutinib inhibits CLL cell survival and proliferation (9), as well as leukemia cell migration toward tissue-homing chemokines (CXCL12, CXCL13) and integrin-mediated CLL cell adhesion (10,11). For patients with CLL, ibrutinib is given orally as a once-daily fixed dose of 420 mg on a continuous schedule until progression or toxicity.…”