BCR-ABL1 Tyrosine Kinase Complex Signaling Transduction: Challenges to Overcome Resistance in Chronic Myeloid Leukemia

Abstract

The constitutively active BCR-ABL1 tyrosine kinase, found in t(9;22)(q34;q11) chromosomal translocation-derived leukemia, initiates an extremely complex signaling transduction cascade that induces a strong state of resistance to chemotherapy. Targeted therapies based on tyrosine kinase inhibitors (TKIs), such as imatinib, dasatinib, nilotinib, bosutinib, and ponatinib, have revolutionized the treatment of BCR-ABL1-driven leukemia, particularly chronic myeloid leukemia (CML). However, TKIs do not cure CML patients, as some develop TKI resistance and the majority relapse upon withdrawal from treatment. Importantly, although BCR-ABL1 tyrosine kinase is necessary to initiate and establish the malignant phenotype of Ph-related leukemia, in the later advanced phase of the disease, BCR-ABL1-independent mechanisms are also in place. Here, we present an overview of the signaling pathways initiated by BCR-ABL1 and discuss the major challenges regarding immunologic/pharmacologic combined therapies.

Keywords: BCR-ABL1; chronic myeloid leukemia; tyrosine kinase inhibitors.

Figure 1

Linear structure of p210 BCR-ABL1 showing the relative position of each domain from both the BCR and the c-ABL portions of the protein. CC, coil-coiled oligomerization domain; STK, serine/threonine kinase domain; Rho/GEF domain; SH, (SRC homology domains) 1, 2, and 3; NTS, nuclear translocation signal; DB, DNA binding domain; AB, actin binding domain.

Figure 2

2D structure of BCR-ABL1 kinase domain and binding sites for TKIs. (A) BCR-ABL1 is a constitutively active kinase that binds ATP and transfers a phosphate from ATP to tyrosine residues on various substrates. This activates downstream signaling pathways, leading to abnormal cellular adhesion and proliferation of myeloid cells and inhibition of apoptosis. TKIs were developed to specifically block the binding of ATP to the BCR-ABL tyrosine kinase, inactivating the constitutive tyrosine kinase activity and inhibiting downstream pathways. (B) Imatinib (first generation TKI) binds to the BCR-ABL kinase domain in its inactive conformation through the ATP binding site. (C) Dasatinib (second generation TKI) inhibits the BCR-ABL tyrosine kinase performance at the ATP site in ABL regardless of protein conformation (active or inactive). (D) Nilotinib (second generation TKI) connects to an inactive conformation of the BCR-ABL protein, taking an analogous region that would be occupied by ATP. (E) Ponatinib (third generation TKI) has multiple contact points for the inactive conformation of the ABL and for the T315I mutation.

Figure 3

Signaling pathways involved in the development of target therapy resistance. (A) Molecular structure of BCR-ABL1 kinase domain with some mutations (indicated in red). (B) Gene amplification can lead to overproduction of tyrosine kinase. (C) Constitutive activation of signaling pathways, such as PI3K-AKT, RAS-MAPK, and JAK-STAT, result in cell proliferation and anti-apoptotic mechanisms. (D) Intracellular concentrations of TKIs can be modified through membrane transporters that may cause increased efflux or decreased influx. (E) The most common chromosome abnormalities involved in karyotype evolution are trisomy 8, trisomy 19, trisomy 21, second Ph chromosome, and isochromosome 17.

Figure 4

List of the most frequent BCR-ABL1 kinase domain mutations resistant to ATP-competitive inhibitors according to their relative relevance.