Mechanisms of Relapse Resistance to Imatinib

Response rates to imatinib in chronic phase patients are quite high and thus far, responses have been durable. Response rates are also quite high in pa-

Is Bcr-Abl present?

Is Bcr-Abl present?

■ Drug efflux • Additional mutations

* Bcr-Abl amplification

■ Kinase mutations

■ Drug efflux • Additional mutations

* Bcr-Abl amplification

■ Kinase mutations

Fig. 1. Scheme for analyzing potential mechanisms of relapse tients with advanced-phase disease, but relapses, despite continued therapy with imatinib, have been common. In all patients who have relapsed, the BCR-ABL protein remains present. A particularly useful categorization of relapsed/resistant CML patients has been to determine whether or not there is persistent inhibition of the BCR-ABL kinase (Fig. 1). Patients with persistent inhibition of the BCR-ABL kinase would be predicted to have additional molecular abnormalities besides BCR-ABL driving the growth and survival of the malignant clone. In contrast, patients with reactivation of the kinase would be postulated to have resistance mechanisms that either prevent ima-tinib from reaching the target or render the target insensitive to BCR-ABL. In the former category are mechanisms such as drug efflux or protein binding of imatinib. In the latter category would be mutations of the BCR-ABL kinase that render BCR-ABL insensitive to imatinib and amplification of the BCR-ABL protein.

In the largest studies of resistance or relapse, several consistent themes have emerged. In the majority of patients who respond to imatinib and then relapse while remaining on therapy, the BCR-ABL kinase has been reactivated (Gorre et al. 2001). BCR-ABL kinase activity was analyzed by assessing tyrosine phosphorylation of CRKL, a direct substrate of the BCR-ABL ki-nase, and the major tyrosine phosphorylated protein in CML patient samples (Oda et al. 1994; Druker et al. 2001b). In these studies, greater than 50% and perhaps as many as 90% of patients with hematologic relapse have BCR-ABL point mutations in at least 13 different amino acids scattered throughout the ABL kinase domain (Hofmann et al. 2001; Branford et al. 2002; Hochhaus et al. 2002; Roche-Lestienne et al. 2002; Shah et al. 2002; von Bubnoff et al. 2002). Some other patients have amplification of BCR-ABL at the genomic or transcript level. In contrast, in patients with primary resis tance, that is, patients who do not respond to imatinib therapy, BCR-ABL-independent mechanisms are most common (Hochhaus et al. 2002).

In patients who relapse due to reactivation of the BCR-ABL kinase, the BCR-ABL kinase remains a good target. Analysis of the inhibitory activity of imatinib against these mutations has shown that some might be sensitive to dose escalation, but the most common mutation at amino acid 315 is completely insensitive to imatinib (Corbin et al. 2002). ABL kinase inhibitors with specificity that differs from imatinib have already been synthesized, and one of these compounds, PD180970, is capable of inhibiting some, but not all of the common BCR-ABL kinase mutations (La Rosee et al. 2002a). These data suggest that it may be possible to treat patients with several different ABL kinase inhibitors to circumvent resistance. Given that BCR-ABL kinase activity has been reactivated in relapsed patients, it might also be useful to target signaling pathways activated by BCR-ABL, such as RAF/ MEK/ERK, PI-3 kinase, AKT, or RAS. For example, two groups recently reported in vitro sensitivity of imatinib-resistant BCR-ABL-positive cell lines to a farnesyl transferase inhibitor (Topaly et al. 2001; Hoover et al. 2002). Moreover, Hoover et al., observed that this compound sensitized cells to imatinib, even imatinib resistant cell lines (Hoover et al. 2002). Alternatively, strategies to decrease BCR-ABL protein expression using agents such as gel-danamycin, 17-AAG, or arsenic trioxide might be useful (Topaly et al. 2001; Gorre et al. 2002; La Rosee et al. 2002b).

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