Targeted Therapy in Chronic Lymphocytic Leukemia

Abstract

Despite a prevailing view that advances in cancer therapy will come through selective targeting of enzymes encoded by mutated oncogenes responsible for the neoplastic phenotype, recent advances in the treatment of patients with chronic lymphocytic leukemia (CLL) have instead exploited knowledge of its biology. Indeed, CLL cells depend on interactions with cells and soluble factors present in the tumor microenvironment for proliferation and survival. B-cell receptor signaling and chemokine-receptor signaling play prominent roles. Elucidation of these signaling pathways has defined physiologic targets for drugs, such as ibrutinib, which inhibit Bruton tyrosine kinase and are therapeutically effective. The characteristic high-level expression of BCL2 in CLL that can enhance leukemia-cell survival has now become an Achilles heel targeted by clinically effective drugs such as venetoclax. Here we discuss advances in such targeted therapy and highlight other disease attributes, such as the distinctive expression of ROR1, which may be targeted for clinical benefit, alone or in combination with other targeted therapies.

FIGURE 1.

Cross-talk and survival-signaling pathways within the leukemia microenvironment.

FIGURE 2.

B-cell receptor signaling triggers formation of a multicomponent “signalosome,” which can activate BTK, AKT, PI3K, PLCγ2, and BLNK, and CD19, a coreceptor important for PI3K activation. Inhibitors target enzymes in this signaling pathway. Modified from Kipps et al.

FIGURE 3.

Cartoon depicting a wrestler representing the antiapoptotic protein BCL2 holding in check the wrestler representing the proapoptotic protein BAX via handholds, which represent the BH3 domains of each protein. Inhibition of BCL2 by binding its BH3 domain frees up the proapoptotic proteins, allowing for release from mitochondria of cytochrome c, which results in apoptosis.

FIGURE 4.

ROR1 signaling in CLL. Adapted from Choi et al.