The Paradigm of Targeting an Oncogenic Tyrosine Kinase: Lesson from BCR-ABL

Abstract

The aberrant tyrosine phosphorylation, either due to constitutive tyrosine kinases (TKs) or to inactivation of protein tyrosine phosphatases (PTPs), is a widespread feature of many cancerous cells. The BCR-ABL fusion protein, which arises from the Philadelphia chromosome, is a molecular distinct and peculiar trait of some kind of leukemia, namely Chronic Myeloid and Acute Lymphoblastic Leukemia, and displays constitutive tyrosine kinase activity. In the chapter, we will highlight the milestones that had led to the identification of the BCR-ABL fusion gene and its role as the only molecular pathogenic event sufficient to elicit and sustain chronic myeloid leukemia. We will also discuss the effort made to unveil the molecular mechanisms of action of the chimeric tyrosine kinase that eventually lead to aberrant cell proliferation and impaired cell-death. Furthermore, we will also review the lesson learned from the selective inhibition of BCR-ABL which currently represent a breakthrough in the treatment of several tumors characterized by defective tyrosine kinase activity.

The Downregulation of Both Giant HERCs, HERC1 and HERC2, Is an Unambiguous Feature of Chronic Myeloid Leukemia, and HERC1 Levels Are Associated with Leukemic Cell Differentiation

“…Later, the second generation of TKIs (e.g., Nilotinib, Dasatinib) was developed with the aim of counteracting the effect of TKI resistance. Currently, TKIs treatment of CML patients has dramatically improved the prognosis of the disease leading to complete remission in the vast majority of patients [4].…”

“…The CML can be effectively treated by selectively targeting BCR-ABL with small molecules tyrosine kinase inhibitors (TKIs), which by inhibiting the kinase activity, drive the cells towards apoptosis. The first tyrosine kinase inhibitor (TKI) developed and successfully used in the clinic was Imatinib [3,4]. Though most CML patients responded very well to Imatinib therapy, a minority relapsed [5].…”

PROTACs: The Future of Leukemia Therapeutics

“…The BCR-ABL oncoprotein is the product of reciprocal chromosomal translocation between the long arms of chromosome 9 and 22 result in the genesis of Chronic Myeloid Leukemia (CML) (Bracco et al, 2021). Its oncogenic properties are a result of its tyrosine kinase activity (Bracco et al, 2021).…”

“…The BCR-ABL oncoprotein is the product of reciprocal chromosomal translocation between the long arms of chromosome 9 and 22 result in the genesis of Chronic Myeloid Leukemia (CML) (Bracco et al, 2021). Its oncogenic properties are a result of its tyrosine kinase activity (Bracco et al, 2021). Generally, BCR-ABL + CML is treated with tyrosine kinase inhibitors (TKIs), usually requiring lifelong administration (T.-T. Huang et al, 2021) (Lai et al, 2015).…”

mTORC2 Is Activated under Hypoxia and Could Support Chronic Myeloid Leukemia Stem Cells

“…Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder characterized by a peculiar cytogenetic abnormality, known as the Philadelphia chromosome (Ph) [ 1 , 2 ]. As a result, part of the breakpoint cluster region ( BCR ) gene fuses with Abelson kinase ( c-ABL ), giving rise to the oncogene BCR-ABL.…”