Abstract
Tyrosine kinases are proteins involved in physiological cell functions including proliferation, differentiation, and survival. However, the dysregulation of tyrosine kinase pathways occurs in malignancy, including hematological leukemias such as chronic myeloid leukemia (CML) and chronic lymphocytic leukemia (CLL). Particularly, the fusion oncoprotein BCR-ABL1 in CML and the B-cell receptor (BCR) signaling pathway in CLL are critical for leukemogenesis. Therapeutic management of these two hematological conditions was fundamentally changed in recent years, making the role of conventional chemotherapy nearly obsolete. The first, second, and third generation inhibitors (imatinib, dasatinib, nilotinib, bosutinib, and ponatinib) of BCR-ABL1 and the allosteric inhibitor asciminib showed deep genetic and molecular remission rates in CML, leading to the evaluation of treatment discontinuation in prospective trials. The irreversible BTK inhibitors (ibrutinib, acalabrutinib, zanubrutinib, tirabrutinib, and spebrutinib) covalently bind to the C481 amino acid of BTK. The reversible BTK inhibitor pirtobrutinib has a different binding site, overcoming resistance associated with mutations at C481. The PI3K inhibitors (idelalisib and duvelisib) are also effective in CLL but are currently less used because of their toxicity profiles. These tyrosine kinase inhibitors are well-tolerated, do have some associated in-class side effects that are manageable, and have remarkably improved outcomes for patients with hematologic malignancies.
Highlights
Tyrosine kinases (TKs) are a large family of surface and intracellular signaling proteins largely conserved in multicellular organisms
In the EURO-SKI trial, the logistic progression model showed that 6 month-TRF is significantly associated with the duration of deep molecular response (DMR, defined as 10,000-fold reduction in B-cell receptor (BCR)-ABL1 transcripts) with tyrosine kinase inhibitor (TKi), as described in Table 3 [63]
The BCR signaling pathway is essential for B-cell survival and proliferation; the loss of one of the key intracellular downstream signaling proteins, Bruton tyrosine kinase (BTK) leads to Bruton’s X-linked agammaglobulinemia (known as X-linked agammaglobulinemia (XLA)), which is a severe immunodeficiency characterized by the developmental arrest of B-cell precursors and no immunoglobulin production [68,69]
Summary
Tyrosine kinases (TKs) are a large family of surface and intracellular signaling proteins largely conserved in multicellular organisms. This kinase family may be subclassified into transmembrane receptors and non-receptor intracellular signaling TKs [1]. Receptor TKs are transmembrane glycoproteins that physiologically interact with extracellular ligands (often growth factors), transducing the signal from the extracellular environment into the cytoplasm, promoting the dimerization of the receptor first and the autophosphorylation of tyrosine residues [2]. Critical TKs include the fusion chimera oncoprotein BCR-ABL1 in CML [8] and the B-cell receptor (BCR) signaling pathway including Bruton Tyrosine Kinase (BTK) [9] and phosphatidylinositol 3-kinase (PI3K) in CLL [10]. We analyze and describe the role of TKs in the pathophysiology of CML and CLL, and the current tyrosine kinase inhibitor (TKi)-based treatments, both in current practice and clinical trials
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