Download in this issue - Cancer Discovery

Published OnlineFirst April 3, 2011; DOI: 10.1158/2159-8290.CD-ITI11-01
Cancer Discovery Publish Ahead of Print, published on April 3, 2011 as doi:10.1158/2159-8290.CD-ITI11-01
Article Name
SECTION
IN THIS ISSUE
KRAS Rearrangements Discovered in Metastatic
Prostate Cancer
• ABRA identifies the first known
translocation of the KRAS
proto-oncogene.
• The fusion protein, UBE2L3-KRAS,
transformed NIH3T3 cells and
altered cellular signaling.
Although KRAS is a commonly
activated proto-oncogene, KRAS
translocations have not been previously observed. Here, Chinnaiyan
and colleagues use a method
termed Amplification Breakpoint
Ranking and Assembly (ABRA)
to identify a fusion between the
KRAS and UBE2L3 genes in the
avana M. Dhanasekaran , Bushra Ateeq , Atsuo T. Sasaki ,
metastatic prostate cancer cell
John R. Prensner , Anastasia K. Yocum , Rui Wang, Daniel
DU145.
KRAS
were also identified in a
hong Cao , Yong Li , Gilbertline
S. Omenn
, Dorothee
Pfluegerrearrangements
,
y Rose Kahoud , Lewis C. Cantley , Mark A. Rubin , Nallasivam
subset
of
metastatic
prostate
cancers.
The UBE2L3-KRAS fuy
, and Arul M. Chinnaiyan
sion includes most of UBE2L3 and all of KRAS, and it induced
1, 3 *
1, 3
1, 3
1, 3
1, 3
1, 3
2
9
1, 3, 6
9, 10
1, 3
9, 10
7, 8
7
• Deregulated Ras-Raf-MAPK signaling may play a role in prostate cancer metastasis.
cell proliferation and focus formation when overexpressed in
NIH3T3 cells. The fusion encouraged growth of tumor xenografts when these cells were implanted into nude mice. In addition, signaling was altered in these cells, with activation of AKT
and p38 MAP kinase (MAPK) observed rather than the more
typical activation of the MEK/ERK pathway. In prostate epithelial cells, the UBE2L3-KRAS fusion was transforming in vitro
and in vivo and mislocalized to late endosomes. This work adds
to a relatively short but growing list of fusion events discovered
in solid tumors and suggests that deregulated RAS-RAF-MAPK
signaling may play a role in metastatic prostate cancer. ≠
1–6
ve genomics approach called amplification breakpoint ranking
ysis, we nominated KRAS as a gene fusion with the ubiquitinU145 cell line, originally derived from prostate cancer metasalysis of tissues revealed that 2 of 62 metastatic prostate
KRAS locus. In DU145 cells, UBE2L3-KRAS produces a fusion
ch attenuates cell invasion and xenograft growth. Ectopic exprotein exhibits transforming activity in NIH 3T3 fibroblasts
vitro and in vivo. In NIH 3T3 cells, UBE2L3-KRAS attenuates
ged by oncogenic mutant KRAS, and instead signals via AKT
inase (MAPK) pathways. This is the first report of a gene futing that this aberration may drive metastatic progression in
See article, p. OF33
The BATTLE Trial: Personalizing Therapy for Lung Cancer
• The BATTLE trial represents a first
step toward personalized therapy
for lung cancer.
ption of an oncogenic gene fusion of KRAS, one of the most studment may represent the driving mutation in a rare subset of metathe importance of RAS-RAF-MAPK signaling in this disease.
gy, 2National
omputational
and 5Urology,
ncer Center,
partments of
nell Medical
ering Cancer
nter, Division
ems Biology,
at Cancer
athology and
dical Center
5-4062; Fax:
INTRODUCTION
To understand the characteristic features of driving gene
fusions in cancer, we previously carried out a large-scale integrative analysis of cancer genomic datasets matched with
gene rearrangement data (1). As part of this analysis, we observed that in many instances a small subset of tumors or
cancer cell lines harboring an oncogenic gene fusion displays
characteristic amplification at the site of genomic rearrangement (refs. 2–6; Supplementary Fig. S1A and B). Such amplifications usually affect a portion of the fusion gene and
are generally considered secondary genetic lesions associated
with disease progression, drug resistance, and poor prognosis (2, 4–8). In contrast, high-level copy number changes that
result in the marked overexpression of oncogenes usually encompass the target genes at the center of overlapping amplifications across a panel of tumor samples. Thus, a “partially”
amplified cancer gene may suggest that this gene participates
• BATTLE is the first prospective,
biopsy-mandated, biomarkerbased, adaptively randomized trial.
Lung cancer is the leading cause of
cancer-related deaths in the United
States. Systemic chemotherapy is
the standard of care for metastatic lung cancer, but targeted
treatments for lung cancer, unlike
those for other cancers, have been
only modestly effective due to
the lack of predictive biomarkers.
The novel design for the phase II
• The BATTLE trial integrates realtime molecular profiling for individualized treatment.
Biomarker-integrated Approaches of Targeted Therapy for Lung
Cancer Elimination (BATTLE) trial includes prospective tumor
biopsy and uses adaptive randomization, based on tumor markers analyzed in real time, to assign patients with non–small cell
lung cancer to the treatment with the greatest potential benefit.
Kim and colleagues report a 46% 8-week disease control rate and
establish the feasibility of a new paradigm for a personalized approach to lung cancer clinical trials. ≠
See article, p. OF42
Lymphocyte and Macrophage Infiltration Predict
Outcome in Breast Cancer
CANCER DISCOVERY. 2011; 1(1) doi: 10.1158/2159-8274.CD-10-0022 | OF33
• Presence of CD8+ CTLs and absence of CD4+ T lymphocytes and
tumor-associated macrophages
(TAM) predicted better outcome.
• Blockade of TAM infiltration
improved sensitivity to chemotherapy and reduced tumor burden in
mouse models.
Recent work has shown that the immune microenvironment
plays an important role in tumor biology. Here, Coussens and
colleagues show that infiltration of certain types of leukocytes
into breast tumor tissue predicts patient survival. In particular,
OF2 | CANCER DISCOVERYAPRIL 2011
• Immunomodulatory agents may
synergize with chemotherapies in
treating breast cancer patients.
high levels of CD8+ CTLs correlated with good outcome,
whereas high levels of CD4+ T lymphocytes and TAMs correlated with poor outcome. Further, the authors found that
the immune signature was predictive of relapse-free survival
www.aacrjournals.org
Copyright
2011 by American Association
Cancer
Downloaded from
cancerdiscovery.aacrjournals.org
on June 17, for
2017.
© 2011Research.
American Association for
Cancer Research.
Published OnlineFirst April 3, 2011; DOI: 10.1158/2159-8290.CD-ITI11-01
IN THIS ISSUE
in patients whose disease had
spread to their lymph nodes.
Because such patients are often treated with chemotherapy,
the authors hypothesized that
the immune microenvironment
might play a role in chemosensitivity. In a mouse model, they
demonstrated that recruitment
of TAMs was a common response of breast cancers to cytotoxic agents. The authors next
demonstrated that treatment of tumor-bearing animals with
SECTION ARTICLE
RESEARCH
See article, p. OF52
Laboratory Screening and Epidemiology Point to
Digoxin as a Possible Therapeutic for Prostate Cancer
• Digoxin is a potent inhibitor
of prostate cancer cell growth
A Novel Two-Stage,
Transdisciplinary Study in vitro.
• Digoxin users in the Health
Professionals Follow-up Study had
25% lower risk of prostate cancer.
Identifies Digoxin as a
Possible Drug for Prostate
Cancer Treatment
Elizabeth A. Platz1–3,*
Srinivasan Yegnasubramanian2,*
Jun O. Liu2,4
Curtis R. Chong4
Joong Sup Shim4
Stacey A. Kenfield5
Meir J. Stampfer5
Walter C. Willett5
Edward Giovannucci5
William G. Nelson2–4
antibodies or a small molecule that inhibited recruitment of
TAMs resulted in improved sensitivity to chemotherapy as
well as reduced primary tumor burden. This result also correlated with increased levels of CD8+ CTLs and a reduction
in metastasis. Finally, the authors show that CD68 and CD8
levels predict response to chemotherapy in human patients.
These data provide evidence that the immune microenvironment is critical in the response to chemotherapy and suggest
that immunomodulatory agents that reduce recruitment of
TAMs might improve sensitivity to chemotherapy. ≠
Is it possible to repurpose already-approved therapeutics for
cancer prevention or treatment?
Platz and colleagues tested over
3,100 compounds, 1,811 of
which are FDA approved, in a
high-throughput screen to determine their effectiveness in slowing the growth of prostate cancer
cell lines. Among the agents not
currently used as anticancer drugs, the class of cardiac glycoside Na+/K+ ATPase inhibitors showed strong inhibition
of cell growth. This class includes digoxin, a drug commonly
• These data motivate future studies
of digoxin as a potential therapy for
prostate cancer.
used to treat heart disease. The authors next examined the
participants in the Health Professionals Follow-up Study, a
large prospective cohort study on risk factors for chronic disease. From these data, they determined that users of digoxin
had a 25% lower risk of prostate cancer than did nonusers.
Although the mechanisms by which cardiac glycosides may
serve as anticancer agents are not clear, this report suggests
that further work is warranted. The article also provides elegant proof-of-principle that the combination of laboratorybased investigations with epidemiologic methods can be a
powerful tool in translational science. ≠
See article, p. OF66
SECTION ARTICLE
RESEARCH
Mutations in the DDR2 Kinase Gene
Identify a Novel Therapeutic Target
in Squamous Cell Lung Cancer
DDR2 Kinase Identified as a Therapeutic Target in
Squamous Cell Carcinoma of the Lung
Peter S. Hammerman1,*
Martin L. Sos2,3,*
Alex H. Ramos4
Chunxiao Xu1
Amit Dutt4
Wenjun Zhou5
Lear E. Brace1
Brittany A. Woods1
Wenchu Lin1
Jianming Zhang5
Xianming Deng5
Sang Min Lim5
Stefanie Heynck2
Martin Peifer2
Jeffrey R. Simard6
Michael S. Lawrence4
Robert C. Onofrio4
Helga B. Salvesen7,8
Danila Seidel2
Thomas Zander3,9
Johannes M. Heuckmann2
Alex Soltermann10
Holger Moch10
Mirjam Koker2
Frauke Leenders2
Franziska Gabler2
Silvia Querings2
Sascha Ansén9
Elisabeth Brambilla11
Christian Brambilla11
Philippe Lorimier11
Odd Terje Brustugun12
Åslaug Helland12
Iver Petersen13
Joachim H. Clement13
Harry Groen14
Wim Timens14
Hannie Sietsma14
Erich Stoelben15
Jürgen Wolf3,9
David G. Beer16
Ming Sound Tsao17
Megan Hanna1,4,18
Charles Hatton1,4,18
Michael J. Eck1
Pasi A. Janne1
Bruce E. Johnson1
Wendy Winckler4
Heidi Greulich1,4
Adam J. Bass1
Jeonghee Cho1
Daniel Rauh6,19
Nathanael S. Gray5
Kwok-Kin Wong1,21
Eric B. Haura20,*
Roman K. Thomas2,3,6,*
Matthew Meyerson1,4,18*
• Tyrosine kinome sequencing identified DDR2 kinase mutations in lung
squamous cell carcinomas (SCC).
• Mutant DDR2 is transforming
in vitro and in vivo, and these
effects are reversed by dasatinib.
Targeted therapies for lung adenocarcinoma have been clinically
successful and are currently generating tremendous excitement.
However, these existing therapies
have little effect on lung SCCs.
To identify new potential targets,
Meyerson and colleagues performed sequencing of the tyrosine
kinome, identifying mutations
in the DDR2 kinase in 3.8% of lung SCCs and SCC cell lines.
Dasatinib, an FDA-approved pharmacologic agent that inhibits
multiple tyrosine kinases including DDR2, inhibited growth of
• Further clinical investigation
of DDR2 as a target in SCC is
warranted.
cell lines harboring mutant DDR2, as did knockdown of the
kinase. Overexpression of mutant DDR2 in cell lines resulted in
classic features of transformation. To validate these results in vivo,
the authors generated a xenograft model by injecting mice with
cell lines harboring DDR2 mutations. Treatment of these mice
with dasatinib decreased tumor size. In a clinical trial of erlotinib
plus dasatinib, one patient harboring a mutation in DDR2 but
with no mutation in epidermal growth factor receptor (the target
of erlotinib) displayed a response. This suggests that further investigation of DDR2 inhibition as a clinical strategy in a subset of
lung squamous cell carcinoma patients is warranted. ≠
See article, p. OF76
APRIL 2011¤CANCER DISCOVERY | OF3
Downloaded from cancerdiscovery.aacrjournals.org on June 17, 2017. © 2011 American Association for
Cancer Research.
Published OnlineFirst April 3, 2011; DOI: 10.1158/2159-8290.CD-ITI11-01
In This Issue
Cancer Discovery Published OnlineFirst April 3, 2011.
Updated version
Supplementary
Material
E-mail alerts
Reprints and
Subscriptions
Permissions
Access the most recent version of this article at:
doi:10.1158/2159-8290.CD-ITI11-01
Access the most recent supplemental material at:
http://cancerdiscovery.aacrjournals.org/content/suppl/2011/03/31/2159-8290.CD-ITI11-01v1.
DC1
Sign up to receive free email-alerts related to this article or journal.
To order reprints of this article or to subscribe to the journal, contact the AACR Publications
Department at [email protected].
To request permission to re-use all or part of this article, contact the AACR Publications
Department at [email protected].
Downloaded from cancerdiscovery.aacrjournals.org on June 17, 2017. © 2011 American Association for
Cancer Research.