Targeting the Resistance in CML

Chronic myelogenous leukemia (CML) and acute promyelocytic leukemia (APL) represent prototypical diseases whose courses have been dramatically changed by the development of targeted forms of therapy. In the case of APL, supra-physiologic concentrations of all trans retinoic acid (ATRA) have been shown to overcome the differentiation block characteristic of the disease both in vitro and in vivo. The pathognomonic lesion of CML is a chromosomal translocation that gives rise to the oncogenic fusion protein Bcr/abl, a tyrosine kinase that signals downstream to multiple pro-survival pathways that collectively confer a survival advantage upon CML cells compared to their normal counterparts. A seminal advance in CML therapy was the rational development of Bcr/abl kinase inhibitors such as imatinib mesylate that trap Bcr/abl in an inactive conformation, resulting in CML cell death.1 Imatinib is highly active in patients with chronic-phase and, to a lesser extent, in accelerated-phase disease. Unfortunately, CML patients can acquire resistance to imatinib through a variety of mechanisms, the most common being development of kinase domain mutations which prevent drug binding. This has led to development of secondgeneration Bcr/abl kinase inhibitors such as nilotinib and the dual Bcr/abl-Src inhibitor dasatinib, which are active against the large majority of kinase mutations2 and have recently been approved for the treatment of imatinib-resistant disease.

Despite these advances, a particularly vexing problem in CML is the appearance of the T315I mutation in the Bcr/abl gatekeeper region. This mutation alters the topology of the ATP binding pocket and disrupts interactions between the protein and not only imatinib, but also nilotinib and dasatinib. Evidence has emerged suggesting that cells bearing the T315I mutation may be present early in the disease and undergo expansion following elimination of their drug-sensitive counterparts. Recently, several multi-kinase inhibitors, including certain aurora kinase inhibitors, have shown activity against T315I mutant cells, but clinical development of such agents has been limited. Clearly, efforts to circumvent the problem of T315I mutations in CML remain a high priority.

In a recent issue of Cancer Cell, O’Hare et al. from the Oregon Health & Science University describe the design and preclinical evaluation of a novel, orally active Bcr/abl kinase inhibitor (AP24534), which displays significant activity against cells bearing T315I and essentially all other Bcr/abl kinase mutations tested, including compound mutations. A unique feature of this agent is its ability to maintain effective hydrophobic contact with the T315I side chain, as well as the potential for multiple protein interaction sites, characteristics which most likely contribute to effectiveness against this and diverse other Bcr/abl mutations. Significantly, AP24534 exposure did not lead to the outgrowth of resistant cells displaying new mutations. It also demonstrated promising activity in xenograft systems, including T315I models. Based upon these promising findings, the results of recently initiated phase I trials of AP24534 are eagerly anticipated.