Evidence that Resistance to Nilotinib May Be Due to BCR-ABL, Pgp, or Src Kinase Overexpression

Abstract

Targeting the tyrosine kinase activity of Bcr-Abl is an attractive therapeutic strategy in chronic myeloid leukemia (CML) and in Bcr-Abl-positive acute lymphoblastic leukemia. Whereas imatinib, a selective inhibitor of Bcr-Abl tyrosine kinase, is now used in frontline therapy for CML, secondgeneration inhibitors of Bcr-Abl tyrosine kinase such as nilotinib or dasatinib have been developed for the treatment of imatinib-resistant or imatinib-intolerant disease. In the current study, we generated nilotinib-resistant cell lines and investigated their mechanism of resistance. Overexpression of BCR-ABL and multidrug resistance gene (MDR-1) were found among the investigated mechanisms. We showed that nilotinib is a substrate of the multidrug resistance gene product, P-glycoprotein, using verapamil or PSC833 to block binding. Up-regulated expression of p53/56 Lyn kinase, both at the mRNA and protein level, was found in one of the resistant cell lines and Lyn silencing by small interfering RNA restored sensitivity to nilotinib. Moreover, failure of nilotinib treatment was accompanied by an increase of Lyn mRNA expression in patients with resistant CML. Two Src kinase inhibitors (PP1 and PP2) partially removed resistance but did not significantly inhibit Bcr-Abl tyrosine kinase activity. In contrast, dasatinib, a dual Bcr-Abl and Src kinase inhibitor, inhibited the phosphorylation of both BCR-ABL and Lyn, and induced apoptosis of the Bcr-Abl cell line overexpressing p53/56 Lyn. Such mechanisms of resistance are close to those observed in imatinib-resistant cell lines and emphasize the critical role of Lyn in nilotinib resistance. [Cancer Res 2008;68(23):9809-16]

Seeking the causes and solutions to imatinib-resistance in chronic myeloid leukemia

“…There is currently conflicting data as to whether nilotinib is a substrate or an inhibitor of the efflux proteins. [55][56][57] Given that intracellular levels of dasatinib increase upon coexposure with nilotinib, there appears to be some degree of active export of dasatinib, but whether this mechanism is clinically relevant remains in doubt. 58 Recently, uptake transporters, especially the organic cation transporter hOCT1, have been investigated as a potential source of imatinib resistance.…”

“…67 Nilotinib-resistant cell lines have also demonstrated Pgp over expression, Abl amplification and Lyn kinase activation, which may signal why some nilotinib-resistant CML cells may remain sensitive to dasatinib. 56 However, the mechanism responsible for many clinical cases of nilotinib resistance remains an ongoing area of research.…”

Breast Cancer Resistance Protein and P-glycoprotein Limit Sorafenib Brain Accumulation

“…However, for a number of tyrosine kinase inhibitors (TKI), including imatinib (2, 3), erlotinib (11), dasatinib (12,13), and lapatinib (14), transport by ABCG2 and P-gp was reported, whereas other TKIs were shown to inhibit ABCG2-and/or P-gp-mediated transport [e.g., gefitinib (15)(16)(17), nilotinib (18,19), and sunitinib (20)]. We therefore anticipated that sorafenib could be a substrate of P-gp and/or ABCG2 as well, and we studied the in vitro transport of sorafenib by human P-gp and ABCG2 and murine Abcg2.…”

The roles of macromolecules in imatinib resistance of chronic myeloid leukemia cells by Fourier transform infrared spectroscopy

“…This is the most important problem in the clinic to get successful results. The molecular mechanisms of multidrug resistance in CML were shown by our group and other researchers [3,4,29]. However, changes in macromolecular levels in imatinib resistant CML cells and the roles of these differences on imatinib resistance were not examined and discussed in the literature.…”