The n e w e ng l a n d j o u r na l of m e dic i n e

clinical implications of basic research

Will Kinase Inhibitors Have a Dark Side?

Charles L. Sawyers, M.D.

A clear lesson that has emerged from growing
experience with small-molecule kinase inhibi-
tors is that a detailed knowledge of the drug tar-
get predicts clinical success in cancer treatment.
Tumors with mutations that activate a kinase (or
other proteins in the signaling pathway in which
the kinase resides) are most likely to respond
when they are treated with an appropriate inhibi-
tor of that particular kinase.
Among the next wave of kinase inhibitors to
be clinically tested are those designed to block
Akt (also called protein kinase B), a molecule with
all the hallmarks of a critical cancer target. The
most compelling evidence comes from genomic
studies of human tumor samples. In one third
to one half of all cancers, such studies have re-
vealed mutations in AKT or in the Akt regulatory
proteins phosphatidylinositol 3-kinase (PI3K)
and phosphatase and tensin homologue (PTEN)
(Fig. 1). A recent report by Yoeli-Lerner et al.,1
however, raises concern. Even though the inhibi-
tion of Akt should foil local tumor growth, it
could promote invasion and metastasis in certain
settings.
The first evidence of a potential antimetastatic
function of Akt was provided by a transgenic
mouse model of breast cancer, as described by
Hutchinson et al.2 As expected, in mice with tu-
mors that overexpress the human epidermal
growth factor receptor 2 (HER2/neu), larger pri-
mary tumors developed in the setting of ramped-
up Akt activity, yet the mice had relatively fewer
metastatic lesions. Yoeli-Lerner et al. confirmed
the antimetastatic action of Akt in several breast-
cancer cell lines and elucidated a potential mech-
anism involving the nuclear factor of activated
T cells (NFAT). The model implicates NFAT as a
master switch that controls the expression of a
set of genes that promotes invasion (Fig. 1). Akt
normally holds NFAT in check by promoting its
destruction in the proteosome, thereby suppress-
ing invasion and metastasis. Akt inhibition allows
NFAT to escape destruction, translocate to the
nucleus, and activate a gene-expression program
that leads to metastasis.
Although the studies by Yoeli-Lerner et al.
and Hutchinson et al. are provocative, should they
have an effect on the clinical evaluation of Akt
inhibitors? It could be argued that they should
not, on the basis of the dismal track record of
preclinical models in the prediction of clinical
outcomes associated with particular cancer drugs.
However, there is growing optimism that genet-
ically defined models, such as those described
in the previously cited studies, may be more pre-
dictive than were earlier approaches. Assuming
that the antimetastatic action of Akt observed in
these breast-cancer models is relevant to human
cancer, how might clinical trials be designed to
detect such a signal?
Initial efficacy trials of Akt inhibitors will
probably be conducted in patients with cancer
who have not had a response to conventional ther-
apy. Clinical activity will be scored by radiographic
assessment of measurable disease and reported
with the use of widely accepted criteria with re-
gard to tumor shrinkage. To increase the proba-
bility of objective responses, much effort will fo-
cus on the enrichment of these trials with patients
whose tumors are suspected to be Akt-dependent.
This strategy is likely to require molecular assess-
ment of tumor-biopsy specimens for abnormal-
ities in AKT or genes encoding other members
of the Akt pathway, since most tumor types have
abnormalities in the Akt pathway only in a
subgroup of cases. If initial clinical trials can
identify patients with Akt-dependent cancers
that shrink during several months of treatment
with an Akt inhibitor, confirmatory phase 2 stud-
ies will be conducted and could lead the Food
and Drug Administration to approve the drug
for use in patients who have no other treatment
options.
If Akt inhibition does enhance metastasis, this
signal will be difficult to detect unless trials are
specifically designed to assess this possibility. Fre-

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 The n e w e ng l a n d j o u r na l of m e dic i n e

Figure 1. The Akt Pathway.

The Akt pathway is frequently activated in certain cancers through mutations in AKT or in the genes encoding other
members of the pathway, such as proteins PI3K and PTEN. PI3K and AKT encode oncogenes (green), whereas PTEN
is a tumor-suppressor gene (red). A recent study by Yoeli-Lerner et al.1 showed that when Akt kinase is active, the
NFAT transcription factor is targeted to the proteosome, where it is degraded. When Akt kinase is inactive (because
of inhibition by a small-molecule drug, for example), NFAT moves to the nucleus, where it drives the expression of
genes that promote invasion and metastasis.

quent radiographic evaluation of patients who
have a response to treatment will not be suffi-
cient for follow-up, because the interpretation of
newly incident lesions will be problematic. With-
out a randomized, untreated control group, it
will be impossible to distinguish between the
promotion of metastasis by Akt inhibition and
normal disease progression. In addition, the ac-
tivation of Akt pathways should be measured in
new lesions to differentiate an effect of the drug
from acquired drug resistance.
Although these concerns may raise fears of
large, expensive, and potentially inconclusive clin-
ical studies, it is worth considering the potential
role of biomarkers to focus the analysis on sub-
groups that are at greatest risk. For example, pa-
tients with NFAT-negative tumors should be at
reduced risk for the prometastatic consequences
of Akt inhibition, since Akt would no longer ex-
ert direct control over the genes controlling in-
vasion. Histologic analysis and genotyping of
tumors could also play a role. On the basis of
models used by Yoeli-Lerner et al. and Hutchin-
son et al., one could conclude that the antimeta-
static actions of Akt may be relevant only in breast
cancer or in tumors driven by HER2. Indeed, stud-
ies in other cell types suggest the opposite — that
Akt inhibition could prevent metastasis in other
types of tumors.
Although the yin–yang biology of Akt sug-
gested by Yoeli-Lerner et al. is unexpected, it is
not without precedent. The transforming growth
factor β–receptor pathway restrains the develop-
ment of tumors in normal epithelium, yet inhibi-
tors of the pathway block tumor growth in mod-
els of late-stage cancer.3 In a similar way, an
inhibitor of a kinase called the mammalian tar-
get of rapamycin (mTOR) blocks Akt-dependent
tumor growth in mouse models but can stimu-
late Akt kinase activity.4,5 Inhibitors of both tar-
gets are being developed for clinical use. At first
glance, the concerns raised by these preclinical
observations are daunting. However, the issues
can be explored in carefully designed clinical tri-

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The New England Journal of Medicine

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 clinical implications of basic research

als with the use of tools of modern genomics,
provided that tissues are collected to allow for
the appropriate measurements to be made.
Dr. Sawyers reports having received consulting fees from
Exelixis. No other potential conflict of interest relevant to this
article was reported.
From the Departments of Medicine, Molecular Pharmacology,
and Urology, University of California, Los Angeles, Los Angeles.
1. Yoeli-Lerner M, Yiu GK, Rabinovitz I, Erhardt P, Jauliac S,
Toker A. Akt blocks breast cancer cell motility and invasion
through the transcription factor NFAT. Mol Cell 2005;20:539-50.
2. Hutchinson JN, Jin J, Cardiff RD, Woodgett JR, Muller WJ.
Activation of Akt-1 (PKB-alpha) can accelerate ErbB-2-mediated
mammary tumorigenesis but suppresses tumor invasion. Cancer
Res 2004;64:3171-8.
3. Arteaga CL. Inhibition of TGFbeta signaling in cancer ther-
apy. Curr Opin Genet Dev 2006;16:30-7.
4. Neshat MS, Mellinghoff IK, Tran C, et al. Enhanced sensitiv-
ity of PTEN-deficient tumors to inhibition of FRAP/mTOR. Proc
Natl Acad Sci U S A 2001;98:10314-9.
5. O’Reilly KE, Rojo F, She QB, et al. mTOR inhibition induces
upstream receptor tyrosine kinase signaling and activates Akt.
Cancer Res 2006;66:1500-8.
Copyright © 2006 Massachusetts Medical Society.

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