Imatinib: Targeted Cancer Therapy

Introduction to Imatinib

Imatinib, under the brand name Gleevec® , is a groundbreaking drug developed for the treatment of specific types of cancer, especially Chronic Myeloid Leukemia (CML). Imatinib belongs to a class of medications called tyrosine kinase inhibitors (TKIs) and works by targeting and inhibiting abnormal tyrosine kinase enzymes.

Imatinib has revolutionised cancer treatment, siginificantly suppressing disease advancement and massively extending patient survival [1].

Imatinib Targeted Therapy for Chronic Myeloid Leukemia

CML pathogenesis is a direct result of the Philadelphia Chromosome. This abnormal chromosome is the result of a translocation mutation. This involves the attachment of the Ableson leukaemia virus 1 (ABL1) gene of chromosome 9 to the breakpoint cluster region (BCR) on chromosome 22.

As a result, the fusion gene BCR-ABL1 is formed which codes for a constitutively active tyrosine kinase. Tyrosine kinases phosphorylate tyrosine residues using ATP. They play key roles in signalling cascades related to cell growth and proliferation. The constitutive nature of this oncogenic protein leads to leukemogenic transformation of hematopoietic stem cells. This is because the malfunctioned kinase is always active, leading to uncontrolled growth and therefore oncogenesis.

CML pathogenesis is a direct result of the uncontrolled tyrosine kinase activity of the oncogenic protein, presenting itself as a clear therapeutic target. Tyrosine kinase inhibitor (TKI) therapy has revolutionised the treatment of CML patients and shows significant improvements in overall survival, prognosis and response rate. Imatinib was the first TKI used for CML treatment and effectively reverses the autophosphorylation of BCR-ABL, inhibiting the successive signalling transduction.

Drawbacks of Imatinib Treatment

However, TKI therapy is suppressive but not curative. TKI susceptibility is maintained only if CML is still dependent on the tyrosine kinases activity of BCR-ABL, seeing that the clinical efficacy of imatinib is based on the on-target inhibition of the kinase domain.

Advanced stage CML progresses independently of BCR-ABL and involves pathways that are driven by mutations to tumour suppressors that are caused by BCR-ABL activity. This renders TKI therapy much less effective as progenitor cell proliferation and survival processes now operate autonomously [2].

More importantly, primitive CML stem cells which are TKI-refractory will retain the disease-causing Ph. Such resistant clones with mutated kinase domains will emerge very rapidly in advanced phase and is a major cause of relapse. This mode of relapse aligns with other active kinase targeted therapy for other cancers [3].

Furthermore, upon removal of the therapy or insufficient dosage, relapse occurs and could progress into advanced disease. Additionally, refractory cells also upregulate genes coding for drug-resistance genes and genes for DNA repair [2]. Therefore, the accumulation of cytogenic and molecular alterations will lead to a point where CML progression no longer requires BCR-ABL activity and first-generation TKI therapy, including imatinib, is no longer effective.

References

1. An X, Tiwari AK, Sun Y, Ding PR, Ashby CR, Chen ZS. BCR-ABL tyrosine kinase inhibitors in the treatment of Philadelphia chromosome positive chronic myeloid leukemia: A review. Leukemia Research. 2010 Oct;34(10):1255-68.
2. Savona M, Talpaz M. Getting to the stem of chronic myeloid leukaemia. Nature Reviews Cancer. 2008 May;8(5):341-50.
3. Braun TP, Eide CA, Druker BJ. Response and Resistance to BCR-ABL1-Targeted Therapies. Cancer Cell. 2020 Apr;37(4):530-42.