| Abstract: |
Bruton’s tyrosine kinase (BTK) is central to the survival of malignant and normal B lymphocytes and has been a crucial therapeutic target of several generations of kinase inhibitors and newly developed degraders. These new means for targeting BTK have added additional agents to the armamentarium for battling cancers dependent on B-cell receptor (BCR) signaling, including chronic lymphocytic leukemia and other non–Hodgkin lymphomas. However, the development of acquired resistance mutations to each of these classes of BTK inhibitors has led to new challenges in targeting BTK as well as novel insights into BCR signaling. The first-generation covalent BTK inhibitor ibrutinib is susceptible to mutations affecting the covalent binding site, cysteine 481 (C481). Newer noncovalent BTK inhibitors, such as pirtobrutinib, overcome C481 mutation–mediated resistance but are susceptible to other kinase domain mutations, particularly at residues Threonine 474 and Leucine 528. In addition, these novel BTK inhibitor resistance mutations have been shown biochemically and in patients to cause cross-resistance to some covalent BTK inhibitors. Importantly, newer generation covalent BTK inhibitors zanubrutinib and acalabrutinib are susceptible to the same mutations that confer resistance to noncovalent inhibitors. The BTK L528W mutation is of particular interest as it disrupts the kinase activity of BTK, rendering it kinase dead. This observation suggests that BTK may act independently of its kinase activity as a scaffold. Thus, the timely development of BTK degrading proteolysis targeting drugs has allowed for degradation, rather than just enzymatic inhibition, of BTK in B-cell lymphomas, and early clinical trials to evaluate BTK degraders are underway. © 2024 American Association for Cancer Research. |
| Keywords: |
signal transduction; genetics; mutation; review; nonhuman; antineoplastic agents; rituximab; flow cytometry; antineoplastic agent; mouse; animal; metabolism; animals; cell death; apoptosis; mantle cell lymphoma; protein kinase inhibitor; protein degradation; waldenstroem macroglobulinemia; drug effect; drug resistance; drug resistance, neoplasm; pyrimidines; protein kinase inhibitors; cytokine; immune response; ubiquitination; systematic review; pyrazole derivative; pyrazoles; cell migration; binding site; cytokine production; piperidines; headache; tumor growth; drug therapy; hematopoietic cell kinase; pyrimidine derivative; cyclin d1; chronic lymphatic leukemia; marginal zone lymphoma; toll like receptor; leukemia, lymphocytic, chronic, b-cell; non-hodgkin lymphoma; stoichiometry; adenine; molecularly targeted therapy; piperidine derivative; molecular targeted therapy; b lymphocyte receptor; ofatumumab; provocation test; bruton tyrosine kinase; small lymphocytic lymphoma; idelalisib; ibrutinib; humans; human; pleckstrin homology domain; ic50; agammaglobulinaemia tyrosine kinase; obinutuzumab; venetoclax; b cell chronic lymphocytic leukemia; zanubrutinib; pirtobrutinib; btk protein, human; nemtabrutinib
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