Nilotinib versus imatinib

Molecular mechanism(s) of its better efficacy


Recently, several reports in Cancer focused on better efficacy of nilotinib than imatinib for the treatment of patients with Philadelphia-positive (Ph+) chronic myeloid leukemia (CML) in the chronic phase.1, 2 We would like to share our experience with imatinib, which could clarify the molecular mechanism(s) of this finding, and to give guidance for further improvement of therapeutic strategy. The effectiveness of both pharmaceutics might be a matter of dose and suppression of telomerase activity in addition to suppression of bcr-abl (breakpoint cluster region/v-abl Abelson murine leukemia viral oncogene) tyrosine kinase. These enzymes are the most powerful key factors in the proliferation and immortalization of cancer cells, and they might be involved with tight cross-signaling.

In the chronic phase of CML, approximately 80% of the patients show reduced telomere length without highly elevated telomerase activity or microsatellite alterations, and in most instances, the Philadelphia translocation is the sole chromosomal anomaly.3 In contrast, in the blast phase of CML, up to 80% of patients show additional cytogenetic changes, resulting in genome instability, enhanced telomerase activity, and telomere dynamics that relate to karyotypic instability. The majority of these patients are already receiving chemotherapy. It has been observed that the telomerase activity has a high prognostic impact in CML and its acceleration associates with shorter survival of the patients.3 It seems that both abnormalities—bcr-abl fusion and telomerase activity—are equally essential for the outcome of disease.

In terms of the effect of imatinib on the telomerase activity and cell proliferation, we found that imatinib has a dual effect on the proliferation of cultured Ph+ cells, derived from patients with CML in the chronic phase, depending on the dose of medication (Fig. 1). In doses above the threshold level, imatinib has an impressive inhibitory effect on cell proliferation, without influencing telomerase activity. In doses below the threshold level, imatinib has a very strong stimulating effect on cell proliferation, which is accompanied with strong telomerase activation.

Figure 1.

Diagram shows the potential mechanism for development of drug resistance in chronic myeloid leukemia. TK indicates tyrosine kinase.

The inhibition of bcr-abl tyrosine kinase in Ph+ cells by imatinib has potential for indirect induction of telomerase activity through regulation of telomeric-associated proteins, namely, overexpession of tankyrase and down-regulation of telomeric repeat binding factor 1 (TRF1)-interacting nuclear factor 2 (Tinf2/TRF1).4 This leads to telomere lengthening and enhancement of cell proliferation. It has been reported that an early strategy to overcome initial standard dose-resistance to imatinib is the use of high doses, which confirms our hypothesis.5

Recently, Shapira and colleagues reported that nilotinib is a telomerase inhibitor.6 Future confirmation of this single report would be of exceptional interest for clarifying the mechanism of cross-signaling between bcr-abl tyrosine kinase and telomerase and its participation in development of drug resistance in CML. The choice of medication dose and effective inhibition of this cross-signaling can be crucial for therapeutic strategy.

Rumiana Bakalova MD, PhD* †, Zhivko Zhelev PhD*, Lubomir Spasov MD†, * Diagnostic Imaging Program, Molecular Imaging Center, National Institute of Radiological Sciences (NIRS), Chiba, Japan, † Medical Faculty, Sofia University, Sofia, Bulgaria.