Resisting the Resistance: Navigating BTK Mutations in Chronic Lymphocytic Leukemia (CLL)

Abstract

Bruton’s tyrosine kinase (BTK) plays a key role in the B-cell receptor (BCR) signaling pathway and confers anti-apoptotic and proliferative properties to malignant B-cells in chronic lymphocytic leukemia (CLL). Small molecule BTK inhibitors were designed to bind BTK’s active site and block downstream signaling. These drugs have now been used in the treatment of thousands of patients with CLL, the most common form of leukemia in the western hemisphere. However, adverse effects of early generations of BTK inhibitors and resistance to treatment have led to the development of newer, more selective and non-covalent BTK inhibitors. As the use of these newer generation BTK inhibitors has increased, novel BTK resistance mutations have come to light. This review aims to discuss previously known and novel BTK mutations, their mechanisms of resistance, and their relationship with patient treatment. Also discussed here are future studies that are needed to investigate the underlying cause allowing these mutations to occur and how they incite resistance. New treatments on the horizon that attempt to maneuver around these resistance mutations can be met with new resistance mutations, creating an unmet need for patients with CLL. Novel therapies and combinations that address all forms of resistance are discussed.

Targeting BTK in B Cell Malignancies: From Mode of Action to Resistance Mechanisms

“…Despite the high efficacy and safety of BTKi treatment, a significant fraction of patients affected by B cell malignancies treated with these drugs experience disease relapse [ 13 , 44 ]. The mechanisms of resistance have been investigated in CLL, MCL, and LPL, while little is known about BTKi resistance in other B cell malignancies.…”

“…The extensive use of BTKi in multiple B cell malignancies over the years has also led to clinical refractoriness in a fraction of cases, prompting the search for the molecular mechanisms underlying clinical refractoriness [ 13 , 44 ]. On these grounds, the aim of this review is to summarize the mode of action of BTKi and the mechanisms of resistance to BTK targeting in B cell malignancies, with a particular focus on CLL, MCL, LPL, and DLBCL.…”

A Review of Resistance Mechanisms to Bruton’s Kinase Inhibitors in Chronic Lymphocytic Leukemia

“…Despite the durable responses of BTKi, many patients suffer from secondary resistance and disease progression [16][17][18][19][20]. In addition, some of them develop Richter's transformation (RT) with an extremely poor prognosis [21][22][23][24][25].…”