Resistance to Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia-From Molecular Mechanisms to Clinical Relevance

Abstract

Resistance to targeted therapies is a complex and multifactorial process that culminates in the selection of a cancer clone with the ability to evade treatment. Chronic myeloid leukemia (CML) was the first malignancy recognized to be associated with a genetic alteration, the t(9;22)(q34;q11). This translocation originates the BCR-ABL1 fusion gene, encoding the cytoplasmic chimeric BCR-ABL1 protein that displays an abnormally high tyrosine kinase activity. Although the vast majority of patients with CML respond to Imatinib, a tyrosine kinase inhibitor (TKI), resistance might occur either de novo or during treatment. In CML, the TKI resistance mechanisms are usually subdivided into BCR-ABL1-dependent and independent mechanisms. Furthermore, patients' compliance/adherence to therapy is critical to CML management. Techniques with enhanced sensitivity like NGS and dPCR, the use of artificial intelligence (AI) techniques, and the development of mathematical modeling and computational prediction methods could reveal the underlying mechanisms of drug resistance and facilitate the design of more effective treatment strategies for improving drug efficacy in CML patients. Here we review the molecular mechanisms and other factors involved in resistance to TKIs in CML and the new methodologies to access these mechanisms, and the therapeutic approaches to circumvent TKI resistance.

Keywords: CML; TKI resistance; bioinformatics and artificial intelligence; epigenetics; immune system; new targeted therapies; patient adherence.

Figure 1

Molecular mechanisms of resistance to TKIs in CML. The molecular mechanisms responsible for TKI resistance in CML include: BCR-ABL1 mutations and BCR-ABL1 overexpression; alteration of DNA damage repair and genomic instability (increasing the additional chromosome abnormalities (ACAs) and point mutations); changes in drug transporters activity (e.g., increased efflux and decreased influx); activation of alternative signaling pathways (e.g., PI3K/AKT, JAK/STAT, and RAS/MAPK); changes in leukemia stem-cell metabolism and pathways (e.g., metabolic shift, Hypoxia/HIF-1α, and Alox5/β-catenin); epigenetic alterations (e.g., mutations on epigenetic regulating genes such as DNMT3A and/or increased methylation of p15 and EBF2 genes); altered expression of microRNAs (e.g., miR-17 and miR-203); changes in the microenvironment and immunological status (e.g., immunosuppressive bone marrow microenvironment (BMM) with increased MDSCs and Treg, plus exhausted T cells).

Figure 2

Alternative to BCR-ABL1 signaling network. To evade BCR-ABL1 inhibition, CML cells activate alternative signaling pathways including RAS/MAPK, SRC, JAK/STAT, WNT/b-catenin, hedgehog, and PI3K/AKT. The transduction of oncogenic signals culminates with the activation of multiple downstream signaling pathways that enhance survival, inhibit of apoptosis, and alter cell adhesion and migration. A subset of these pathways and their constituent transcription factors (β-catenin, Gli, STAT5, MYC, FOXO3), serine/threonine-specific kinases (RAS/MAPKs, PI3K/AKT/mTOR), and apoptosis-related proteins (BAD, BCL-2, BCL-XL, survivin) are shown. It is important to note that this is a simplified diagram and that many more associations between BCR-ABL1 and signaling proteins have been reported.