Response and Resistance to BCR-ABL1-Targeted Therapies

Abstract

Chronic myeloid leukemia (CML), caused by constitutively active BCR-ABL1 fusion tyrosine kinase, has served as a paradigm for successful application of molecularly targeted cancer therapy. The development of the tyrosine kinase inhibitor (TKI) imatinib allows patients with CML to experience near-normal life expectancy. Specific point mutations that decrease drug binding affinity can produce TKI resistance, and second- and third-generation TKIs largely mitigate this problem. Some patients develop TKI resistance without known resistance mutations, with significant heterogeneity in the underlying mechanism, but this is relatively uncommon, with the majority of patients with chronic phase CML achieving long-term disease control. In contrast, responses to TKI treatment are short lived in advanced phases of the disease or in BCR-ABL1-positive acute lymphoblastic leukemia, with relapse driven by both BCR-ABL1 kinase-dependent and -independent mechanisms. Additionally, the frontline CML treatment with second-generation TKIs produces deeper molecular responses, driving disease burden below the detection limit for a greater number of patients. For patients with deep molecular responses, up to half have been able to discontinue therapy. Current efforts are focused on identifying therapeutic strategies to drive deeper molecular responses, enabling more patients to attempt TKI discontinuation.

Keywords: BCR-ABL; CML; targeted therapy; tyrosine kinase inhibitor.

Figure 1.. Molecular Pathway Activation Downstream of BCR-ABL1

BCR-ABL1 dimerizes leading to autophosphorylation at tyrosine 177 of BCR. This serves as a docking point for the GRB2/GAB2/SOS complex which activates multiple signaling pathways, including PI3K/AKT and MAPK. Autophosphorylation of key residues in the BCR-ABL1 kinase domain also in turn activate the JAK/STAT pathway likely via activation of JAK2 and direct phosphorylation of STAT5. In the setting of BCR-ABL1 TKI resistance, extracellular growth factors can act via the JAK/STAT pathway to sustain cell growth. Leukemia stem cells may uniquely depend on WNT/β-catenin and SHH/SMO signaling for survival in the face of BCR-ABL1 kinase inhibition.

Figure 2.. Monitoring of Chronic-Phase CML on BCR-ABL1 TKI Therapy

BCR-ABL1 transcript levels as measured by reverse-transcriptase PCR and their corresponding disease status. Risk of relapse per year numbers are derived from the original IRIS trial and subsequent European LeukemiaNet guidelines (Hughes et al., 2003; Marin et al., 2008).

Figure 3.. BCR-ABL1 Tyrosine Kinase Inhibitors and Resistance Mechanisms

Chemical structures and published X-ray crystallographic structures of ABL1 complexed with kinase inhibitors are shown. Residues at which mutations are associated with strong resistance to a given TKI are indicated in red, while those associated with lesser degrees of resistance are listed in orange. Both T315 and E255 mutations do lead to an increase in the IC₅₀ for ponatinib; however, they do not typically lead to clinical resistance in isolation, but do as a compound mutation. The structure of ABL1 complexed with asciminib shows nilotinib in the ATP-binding site for reference. T315I is indicated in purple for visual reference (Cowan-Jacob et al., 2007; Levinson and Boxer, 2012; O’Hare et al., 2009; Tokarski et al., 2006; Weisberg et al., 2005; Wylie et al., 2017).

Figure 4.. BCR-ABL1 Transcript Levels in a CML Patient in Long-Term Treatment-free Remission

Example of an individual who underwent imatinib discontinuation in 2011 and has maintained a TFR since that time with fluctuating BCR-ABL1 PCR levels but maintenance of an MMR.