Nilotinib is a new oral tyrosine kinase inhibitors (TKI), rationally designed to overcome imatinib resistance in chronic myelogenous leukemia (CML). In Phase I and II studies, nilotinib achieved good tolerability and durable responses in adult patients with Ph+ CML resistant or intolerant to at least one prior therapy, including imatinib. This subsequently resulted in the approval of nilotinib for the treatment of patients with newly diagnosed CML or imatinib-resistant/-intolerant patients with chronic or accelerated-phase CML. In addition to inhibiting BCR-ABL, nilotinib, similar to imatinib, also has potent activity against the DDR, KIT, PDGFR, and colony stimulating factor receptor-1 (CSF-1R) tyrosine kinases. Mutations in the genes encoding for these tyrosine kinases have been shown to play a key role in the pathogenesis of certain malignancies, including gastrointestinal stromal tumors (GIST), subtypes of melanoma, and pigmented villonodular synovitis (PVNS). This article will introduce the mechanism of action of nilotinib in GIST and PVNS.^[1]

In GIST

Because of its chemical structure, nilotinib has demonstrated anticancer activity in CML through its ability to selectively inhibit autophosphorylation of BCR-ABL. Small changes in the mode of binding to ABL enable nilotinib to inhibit cellular proliferation of imatinib-sensitive and -resistant CML cell lines more potently than imatinib. Additional preclinical work indicated that the anticancer activity of nilotinib in CML is antiproliferative rather than proapototic.

Although nilotinib was not rationally designed specifically to treat GIST, its in vitro activity against kinases other than BCR-ABL, particularly KIT- and PDGFRα (both of which are known to be oncogenic in GIST) led to its evaluation in this setting. Specific oncogenic mutations within the KIT or PDGFRα receptor tyrosine kinase lead to constitutive phosphorylation and activation of the receptor resulting in uncontrolled cellular proliferation and the subsequent development of several human malignancies, including GIST. Four different regions of KIT are known to be mutated in GIST, and of these the juxtamembrane portion coded for by exon 11 is most often affected (~67% of GIST), followed by mutations in exon 9 (~10%), exon 13 (~1–2%), and exon 17 (~1%). Across all known mutation types, approximately 80% of GIST harbor mutations in KIT, while 5–8% have mutations in PDGFRA and 12–15% are wild-type.

In PVNS

In addition to the BCR-ABL, KIT, and PDGFR kinases, nilotinib has also shown in vitro activity against CSF1R, albeit weaker than that of imatinib, which is strongly expressed in PVNS. This benign but painful neoplastic condition, also known as tenosynovial giant cell tumor (TGCT), affects the synovium in young and middle-aged adults with the potential for severe joint morbidity and results from a specific alteration that affects the CSF1 gene. Inhibition of CSF-1R with imatinib has been reported to produce tumor remission in patients with PVNS, suggesting that targeting this pathway can provide additional treatment options beyond surgery for this tumor type. Nilotinib is being investigated for this indication.

Reference

[1] Nilotinib: A Novel, Selective Tyrosine Kinase Inhibitor. DOI:10.1053/j.seminoncol.2011.01.016