New pieces in the BTKi resistance puzzle

Abstract

In this issue of Blood, Chen et al1 report about novel mechanisms of ibrutinib resistance related to BTK Cys481 point mutations in Waldenström macro-globulinemia (WM). They transfected WM and diffuse large B-cell lymphoma (DLBCL) cells with vectors containing wild-type (BTKWT) or Cys481Ser mutated (BTKCys481Ser) BTK, and examined effects of the transfected genes on ibrutinib sensitivity and signaling pathways, especially on ERK activation. The authors report that BTKCys481Ser promotes ibrutinib resistance via reactivation of ERK1/2 signaling (see figure). Next, they examined how WM and DLBCL cells carrying BTKCys481Ser can confer survival benefit to BTKWT cells, an important question because BTK resistance mutations often only affect a sub-population of the malignant B cells. A prosurvival effect on WT cells was seen when mixing mutated and WT cells, which apparently did not depend on cell-cell contact, as demonstrated in micropore filter experiments to separate BTKWT from BTKCys481Ser cells. In this setting, BTKCys481Ser cells still conferred protection of BTKWT cells in a paracrine fashion, via secretion of cytokines, especially interleukin-6 (IL-6) and IL-10, which were found to be elevated in supernatants from BTKCys481Se but not from BTKWT cells.