Steven Grant, MD
2010-01-01
Dr. Grant indicated no
relevant conflicts of interest.
O’Hare
T, Shakespeare WC, Zhu X, et al. AP24534,
a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the
T315I mutant and overcomes mutation-based resistance. Cancer Cell.
200;401-12.
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.
The significance of
these findings is that, just as in the case of imatinib development, which
demonstrated the feasibility of a rational, structure-based approach to the
treatment of an oncogene-addicted disease like CML, the
prospect of applying precisely the same principles to circumventing resistance
represents a very real possibility. Of course, numerous questions remain to be
answered. For example, will unanticipated toxicities limit AP24534 activity?
Will AP24534 resistance develop in vivo, including Bcr/abl-independent forms
of resistance? Will AP24534 effectively eradicate CML stem cells? One thing is
for certain: This rational approach to the problem of drug resistance may serve
as a paradigm for future efforts in the hematologic as well as the
non-hematologic malignancy fields.
- Druker BJ. Translation
of the Philadelphia chromosome into therapy for CML. Blood. 2008;4808-17.
- Quintás-Cardama A, Kantarjian H, Cortes J. Flying
under the radar: the new wave of BCR-ABL inhibitors. Nat
Rev Drug Discov. 2007;834-48.
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