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JULY 2014�CANCER DISCOVERY | 745
IN THIS ISSUEIN THIS ISSUE
Dissemination of cancer cells
from primary tumors has been
shown to occur early during
tumor growth in both breast and
pancreatic cancer, suggesting that
these cancer cells already possess
the genetic changes required
to initiate the metastatic cas-
cade. However, it is not known
whether early premalignant lung
lesions are also inherently capable of generating disseminated
tumor cells (DTC). To analyze lung cancer cell dissemination,
Caswell and colleagues utilized a genetically engineered mouse
model of lung cancer driven by Kras mutation in which tumor
cells were fl uorescently labeled. Intriguingly, few DTCs were
detected in Kras-mutant mice with either early-stage hyper-
plastic lesions or adenocarcinomas. Concomitant loss of p53
was associated with the presence of DTCs in a fraction of mice
with late-stage lung tumors, suggesting that p53 inactivation
is not suffi cient to facilitate dissemination but enables the
acquisition of additional genetic changes necessary to trigger
dissemination. These DTCs originated from a single primary
tumor, indicative of cell-autonomous alterations that confer
the ability to disseminate. In addition, DTCs exhibited reduced
expression of the prodifferentiation transcription factor Nkx2-
1, which was also downregulated in a portion of the parental
tumor cells coincident with increased proliferative potential,
supporting the notion that loss of Nkx2-1 in a subpopulation
of primary tumor cells promotes the generation of DTCs.
These results suggest that dissemination is an acquired phe-
notype in lung adenocarcinoma and a rate-limiting barrier to
lung cancer metastasis. ■
See article, p. 781.
• Kras-mutant, p53-deficient tumor
cells are not inherently capable of
dissemination in mice.
• p53 loss is insufficient to drive dis-
semination but enables acquisition
of required alterations.
• Nkx2-1 downregulation and
enhanced proliferation in primary
tumors precede dissemination.
Dissemination Is a Barrier to Lung Cancer Metastasis
Autophagy has been implicated
in tumorigenesis given its ability
to promote cancer cell survival
during stress, and the activating
BRAF V600E mutation is known to
enhance basal autophagic activ-
ity in diverse tumor types. The
BRAF V600E mutation has recently
been identifi ed in pediatric central
nervous system (CNS) tumors,
but whether autophagy contributes to BRAF V600E-induced
tumorigenesis in these tumor types is not fully understood.
Mulcahy Levy and colleagues found that BRAF V600E-positive
CNS tumor cell lines exhibited greater starvation-induced
autophagy than did BRAF–wild-type CNS tumor cells, raising
the possibility that the increased autophagy associated with
BRAF V600E might contribute a selective advantage to CNS
tumor cells. Indeed, genetic or pharmacologic inhibition of
autophagy was cytotoxic to BRAF-mutant CNS tumor cells,
but had a minimal effect on survival of BRAF–wild-type cells,
indicating that BRAF-mutant CNS tumor cells are depend-
ent on autophagy for survival. Moreover, treatment with the
autophagy inhibitor chloroquine improved the effectiveness
of both standard chemotherapeutics and the BRAF inhibitor
vemurafenib, and showed synergistic activity with vemuraf-
enib in BRAF-mutant CNS tumor cells at clinically achievable
doses. Of note, combined chloroquine and vemurafenib treat-
ment overcame vemurafenib resistance in primary BRAF V600E-
positive pleomorphic xanthoastrocytoma cells and led to rapid
clinical improvement and stabilization of disease in a patient
with vemurafenib-refractory BRAF V600E-positive brainstem
ganglioglioma that reversed whenever vemurafenib was discon-
tinued. These fi ndings indicating that BRAF-mutant pediatric
CNS tumors are autophagy-dependent provide a rationale for
combining autophagy inhibitors with BRAF-targeted therapy
in patients with relapsed or refractory disease. ■
See article, p. 773.
• Genetic or pharmacologic inhibition
of autophagy is cytotoxic to
BRAFV600E-positive CNS tumor cells.
• Chloroquine synergizes with vemu-
rafenib or standard chemotherapy
in BRAF-mutant CNS tumor cells.
• A child with relapsed BRAF-mutant
ganglioglioma responded to chloro-
quine plus vemurafenib therapy.
Autophagy Inhibition Targets BRAF-Mutant Pediatric CNS Tumors
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746 | CANCER DISCOVERY�JULY 2014 www.aacrjournals.org
IN THIS ISSUE
Dormant residual breast can-
cer cells often persist for long
periods following treatment and
can give rise to incurable recur-
rent tumors, emphasizing the
need to understand the molecu-
lar mechanisms that regulate the
outgrowth of these cells. Using
genetically engineered mouse
models, Feng and colleagues
found that SplA/ryanodine receptor domain and SOCS box
containing 1 (SPSB1) is upregulated in recurrent mammary
tumors and was both necessary and suffi cient for tumor recur-
rence following suppression of the driving HER2/neu onco-
gene. SPSB1 expression protected both murine and human
mammary tumor cells from apoptosis in response to HER2/
neu inhibition or treatment with chemotherapeutic agents
and was selected for during tumor outgrowth, indicating that
SPSB1 confers a growth advantage in residual breast cancer
cells. The prosurvival function of SPSB1 was dependent on
binding of SPSB1 to c-MET and potentiation of c-MET activity
in the absence of HER2/neu expression, as inhibition of c-MET
diminished breast cancer cell viability and prevented selection
of SPSB1-expressing cells in tumor-bearing mice. Furthermore,
elevated SPSB1 expression was associated with basal-like breast
cancer and was independently correlated with increased risk of
relapse only in patients with increased c-MET expression and
activity, suggesting that SPSB1 may contribute to the aggres-
sive phenotype and therapeutic resistance in these tumors via
activation of c-MET signaling. These fi ndings defi ne a role for
SPSB1-driven c-MET activity in breast cancer recurrence and
suggest that targeting SPSB1 may limit tumor relapse. ■
See article, p. 790.
• SPSB1 upregulation is necessary
and sufficient for breast cancer
recurrence in mouse models.
• SPSB1 protects breast cancer cells
from apoptosis following HER2
inhibition or chemotherapy.
• Potentiation of c-MET signaling is
required for SPSB1-driven tumor
cell survival and recurrence.
SPSB1-Mediated c-MET Activation Drives Breast Cancer Recurrence
Women with a family history
of breast cancer have a 2- to 3-fold
higher risk of developing the
disease. Currently, only approxi-
mately 50% of familial breast
cancers can be attributed to
mutations in known cancer sus-
ceptibility genes, such as BRCA1
or BRCA2, which suggests that
additional genetic mutations
may confer hereditary breast cancer risk. Park and colleagues
used whole-exome sequencing to screen for previously unrec-
ognized cancer susceptibility genes in a cohort of 89 women
with early-onset breast cancer from highly selected families
with multiple cases of breast cancer. This approach iden-
tifi ed three separate, family-specifi c mutations in RAD50-
interacting protein 1 (RINT1) that were not observed in public
databases. In line with these fi ndings, case–control mutation
screening showed an enrichment of RINT1 variants that were
predicted to be deleterious in women with early-onset breast
cancer compared with age-matched controls, and an addi-
tional 4 RINT1 mutations were identifi ed in an independent
large cohort of multicase breast cancer families. Variants in
RINT1 that were likely to be pathogenic included missense
mutations, in-frame deletions, and mutations predicted to
affect RINT1 splicing. Of note, comparisons of cancer inci-
dence across RINT1 mutation–positive families revealed a sig-
nifi cantly higher risk for Lynch Syndrome–spectrum cancers
that are associated with DNA mismatch repair defects. These
fi ndings implicating RINT1 as a breast cancer susceptibility
gene suggest that RINT1 should be added to the list of genes
evaluated in genetic testing for hereditary breast cancer. ■
See article, p. 804.
• RAD50-interacting protein 1 (RINT1)
mutations were identified in women from
multiple-case breast cancer families.
• Rare RINT1 variants were enriched
in early-onset breast cancer cases com-
pared with unaffected female controls.
• Carriers of RINT1 mutations also
display a higher incidence of Lynch
Syndrome–spectrum cancers.
RINT1 Is a Breast Cancer Predisposition Gene
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JULY 2014�CANCER DISCOVERY | 747
IN THIS ISSUE
Inhibitors targeting the MAPK
pathway are clinically effective
in the majority of patients with
BRAF-mutant melanoma; how-
ever, a subset of patients fails to
respond due to intrinsic resist-
ance mechanisms that remain
poorly understood. Koniecz-
kowski and colleagues found
that MAPK inhibitor–sensitive
and intrinsically resistant melanoma cell lines and tumors
were defi ned by distinct and reciprocal gene expression pro-
fi les, suggesting that cell-autonomous differences contrib-
ute to RAF and MEK inhibitor drug resistance. Specifi cally,
intrinsically resistant melanomas were characterized by
low expression and activity of microphthalmia-associated
transcription factor (MITF) and elevated NF-κB pathway
signaling (MITF-low/NF-κB–high), whereas MAPK inhibi-
tor–sensitive melanomas were classifi ed as MITF-high/
NF-κB–low. Establishment of these two transcriptional
states in melanocytes was regulated by the balance between
oncogenic MAPK signaling, which activated NF-κB, and
sustained MITF expression. Stimulation of NF-κB activity
in MAPK inhibitor–sensitive cells induced a transition to
the MITF-low/NF-κB–high phenotype by suppressing MITF
and was suffi cient to confer resistance to MAPK pathway
inhibitors, indicative of plasticity between these states. Fur-
thermore, inhibition of BRAF in MITF-high, drug-sensitive
cells was associated with a transition to the MITF-low/
NF-κB–high state, suggesting that this phenotype correlates
with reduced dependence on MAPK signaling and may also
contribute to acquired MAPK inhibitor resistance. These
results identify transcriptional states that may underlie
intrinsic resistance to MAPK inhibition and may help to
predict therapeutic responses among patients with BRAF-
mutant melanoma. ■
See article, p. 816.
• Reciprocal MITF and NF-κB activity
defines MAPK inhibitor–sensitive
and resistant melanomas.
• High NF-κB activity suppresses
MITF and confers intrinsic resis-
tance to MAPK inhibitors.
• Transition to an MITF-low/NF-κB–
high state may contribute to ac-
quired MAPK inhibitor resistance.
Transcription States Are Linked to Intrinsic Drug Resistance in Melanoma
Several cancers such as
gliomas and acute myeloid
leukemias harbor recurrent neo-
morphic mutations in isocitrate
dehydrogenase 1 or 2 (IDH1/2)
that cause the enzyme to con-
vert α-ketoglutarate (αKG) to
2-hydroxyglutarate (2HG), an
oncometabolite that modulates
αKG-dependent DNA and his-
tone demethylases and promotes cellular transformation.
To identify drugs that can reduce 2HG production, Elham-
mali and colleagues screened a library of compounds using
a high-throughput fl uorimetric assay that measured 2HG
levels in IDH1-mutant cells. The most potent compound
identifi ed by the screen was Zaprinast, a known inhibitor
of phosphodiesterase type 5 (PDE5). However, Zaprinast
did not reduce 2HG levels through inhibition of PDE5 but
instead acted through an off-target effect on glutaminase,
an enzyme that operates upstream of mutant IDH. Zap-
rinast noncompetitively inhibited glutaminase, preventing
the enzyme from metabolizing glutamine into glutamate,
a precursor of the mutant IDH substrate αKG. Accord-
ingly, Zaprinast reduced DNA and histone methylation
and prevented soft-agar colony formation in IDH1-mutant
cells, suggesting that this compound could reverse the
mutant IDH phenotype. Additionally, Zaprinast increased
levels of reactive oxygen species, enhanced susceptibility to
oxidative damage, and reduced growth in pancreatic ductal
adenocarcinoma cells that are dependent upon glutamine
metabolism. Although clinically useful dosages of Zapri-
nast may not be achievable given its higher potency against
PDE5 than glutaminase, these fi ndings raise the possibility
that Zaprinast or more glutaminase-selective Zaprinast
derivatives may have activity in IDH-mutant or glutamine-
addicted cancers. ■
See article, p. 828.
• A fluorimetric assay was used in a
screen for drugs that reduce cellu-
lar levels of 2-hydroxyglutarate.
• Zaprinast blocks 2-hydroxygluta-
rate production through noncom-
petitive inhibition of glutaminase.
• IDH1-mutant and glutamine-ad-
dicted cancer cells are both sensi-
tive to Zaprinast.
Zaprinast Blocks 2-Hydroxyglutarate Production by Inhibiting Glutaminase
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748 | CANCER DISCOVERY�JULY 2014 www.aacrjournals.org
IN THIS ISSUE
Disruption of the tumor sup-
pressor gene RB1 conforms to
the classical two-hit model, in
which mutation followed by
LOH promotes tumor forma-
tion. In addition to its role in
cell-cycle progression, the RB
protein (pRB) has also been sug-
gested to participate in DNA
replication, DNA repair, and
chromosome condensation, but the mechanism by which
pRB regulates genome stability remains unclear. Coschi and
colleagues found that loss of pRB or expression of a mutant
pRB enhanced γH2AX foci formation and triggered aberrant
DNA replication, particularly at major satellite repeats within
pericentromeric chromatin, indicative of replication stress.
Replication of pericentromeres was regulated by formation
of a complex between pRB, E2F1, and condensin II at major
satellite repeats. Intriguingly, loss of a single Rb1 allele reduced
condensin II recruitment to pericentromeres, induced γH2AX
deposition to a level similar to that of Rb1-defi cient cells, and
resulted in mitotic errors and chromosome structure defects,
suggesting that Rb1 is haploinsuffi cient for maintenance
of genome stability. Consistent with this idea, γH2AX foci
and mitotic defects were also enhanced in normal RB1+/−
fi broblasts from patients with hereditary retinoblastoma,
and RB1+/− cancer cell lines of mesenchymal origin harbored
increased chromosomal abnormalities, similar to RB1−/− cells.
Furthermore, tumors isolated from mice heterozygous for
mutant Rb1 exhibited increased chromosomal gains and
losses. These results identify a gene dosage–dependent func-
tion of pRB in suppressing genome instability and suggest
that disruption of this function contributes to aneuploidy
in cancer. ■
See article, p. 840.
• A pRB–E2F1–condensin II complex
regulates DNA replication at peri-
centromeric chromatin.
• Loss of a single RB1 allele induces
replication stress and defects in
chromosome segregation.
• RB1 haploinsufficiency results in
aneuploidy that may contribute to
tumor formation.
pRB Regulates Genome Stability in a Dosage-Sensitive Manner
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