Targeting the BCR signalosome in B cell malignancies

Chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), and Waldenström macroglobulinemia (WM) are B-cell malignancies which are still incurable. In these lymphomas, the cells proliferate in specialized niches in lymph nodes and bone marrow, in which they are provided by stromal-derived growth and survival factors. At least for CLL and MCL, several studies indicate that the B-cell antigen receptor (BCR) is activated in these niches. The first clinical trials with the novel BCR signalosome inhibitors ibrutinib (BTK inhibitor), idelalisib (PI3Kδ inhibitor), and fostamatinib (SYK inhibitor) were very promising. However, although a rapid and sustained reduction of lymphadenopathy was observed in the patients, this was unexpectedly accompanied by (transient) lymphocytosis. We studied the mechanism of action of ibrutinib at a molecular and cellular level. We observed that ibrutinib did not target the viability of CLL, MCL, and WM cells in a direct manner, but it strongly inhibited BCR-controlled signaling and integrin-mediated adhesion. Furthermore, ibrutinib partially inhibited chemokine-induced signaling, adhesion, and migration of CLL and MCL cells. Idelalisib was also able to inhibit BCR-controlled integrin-mediated adhesion, and in combination with ibrutinib this inhibition was strongly synergistic in CLL and MCL. Thus, our findings indicate that inhibition of the BCR signalosome overcomes BCR-controlled integrin-mediated retention of the malignant CLL, MCL, and WM cells in their growth- and survival-supporting lymphoid tissue microenvironment, which results in clinically evident disease regression. Furthermore, our preclinical studies indicate that the combination of ibrutinib and idelalisib is beneficial to the patients and may prevent drug-resistance.