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Published OnlineFirst November 6, 2014; DOI: 10.1158/2159-8290.CD-RW2014-231
RESEARCH WATCH
Chemotherapy
Major finding: The efficacy of anthracycline chemotherapy depends on activation of type I IFN immune responses.
Mechanism: Anthracyclines induce TLR3mediated type I IFN–IFNAR signaling and
CXCL10 secretion by cancer cells.
Impact: High expression of a type I IFN
signature may predict successful anthracycline-based chemotherapy.
TYPE I IFN SIGNALING IN CANCER CELLS ENHANCES CHEMOTHERAPY RESPONSES
Anthracyclines are effective chemotherapeutic agents that
function in part by eliciting anticancer immune responses. Sistigu, Yamazaki, Vacchelli, and colleagues hypothesized that the
activity of anthracyclines may require type I IFN signaling, which
is essential for the immune response to viral infections. Consistent with this idea, global transcriptome profi ling of murine
fibrosarcomas revealed that doxorubicin treatment increased
the expression of IFN-stimulated genes associated with viral
infection in neoplastic cells. Signaling of IFNαβ through the
type I IFN receptor, IFNAR, in neoplastic but not host cells
was required for the antitumor effects of anthracyclines. In
addition, sarcomas deficient in toll-like receptor 3 (TLR3), an
endosomal pattern recognition receptor, failed to instigate a
type I IFN fingerprint following doxorubicin treatment and were
unable to respond to anthracycline-based chemotherapy, suggesting that TLR3 activation by self-RNA released from dying
cells is necessary for anthracycline-induced production of type I
IFNs. In response to anthracyclines, type I IFN–IFNAR signaling
stimulated autocrine and paracrine signaling and secretion of
chemokine (C-X-C motif) ligand 10 (CXCL10), which plays an
important role in antiviral and type I IFN immune responses,
by both mouse and human tumor cells. Blockade of CXCL10
signaling abrogated the antitumor efficacy of doxorubicin,
whereas administration of recombinant CXCL10 was sufficient
to restore the sensitivity of IFNAR- and TLR-deficient sarcoma
cells to doxorubicin. Exogenous type I IFNs also enhanced the
sensitivity of tumor cells to cisplatin chemotherapy by stimulating protective IFNAR-mediated immune responses. Furthermore, high expression of a type I IFN signature was predictive
of pathologic complete response to neoadjuvant anthracyclinebased chemotherapy in patients with breast carcinoma and was
associated with increased metastasis-free survival in patients
with poor prognosis. These data demonstrate that anthracyclines mimic viral infection to induce optimal chemotherapeutic
responses and suggest that type I IFN signaling may represent a
useful clinical biomarker. ■
Sistigu A, Yamazaki T, Vacchelli E, Chaba K, Enot DP, Adam J, et al.
Cancer cell–autonomous contribution of type I interferon signaling to the
efficacy of chemotherapy. Nat Med 2014;20:1301–9.
Targeted Therapy
Major finding: GADD45β/MKK7 is critical for NFκB-driven survival and is a
therapeutic target in multiple myeloma.
Mechanism: Disruption of the GADD45β/
MKK7 complex induces proapoptotic
JNK signaling in multiple myeloma cells.
Impact: Inhibition of GADD45β/MKK7
selectively blocks NFκB-mediated
survival in certain cancer cells.
TARGETING GADD45b/MKK7 DOWNSTREAM OF NFkB INDUCES CANCER-SPECIFIC APOPTOSIS
Many cancers, including multiple myeloma,
exhibit aberrant activation of NFκB signaling, which
promotes cancer-cell survival via the upregulation
of antiapoptotic genes and renders cells sensitive
to NFκB inhibition. However, to date, no NFκBtargeted therapies have been clinically approved due
to toxicities associated with global NFκB inhibition, underscoring the need to develop strategies
to selectively inhibit cancer-specific NFκB signaling. Tornatore and colleagues found that expression of the NFκB target
gene growth arrest and DNA-damage–inducible β (GADD45B),
which encodes an inhibitor of the JNK kinase MKK7 (also
known as MAP2K7), was elevated in plasma cells from patients
with multiple myeloma and was correlated with decreased
survival. GADD45β was essential for NFκB-mediated survival
of multiple myeloma cells through inhibition of MKK7–JNKdriven apoptosis, suggesting GADD45β as a potential therapeutic target. A peptide library screen identified two acetylated
L-tetrapeptides that disrupted the GADD45β/MKK7 complex
in vitro. Synthesis of the corresponding D-tetrapeptides and
subsequent chemical optimization yielded DTP3, a highly stable D-tripeptide with improved bioavailability that interacted
specifically with MKK7 to activate JNK signaling
and induce cancer-cell–specific apoptosis in a dosedependent manner. DTP3 also displayed potent and
selective activity in various cancer cell lines with
high GADD45B expression. Importantly, DTP3 was
cytotoxic to primary myeloma cells from patients
at low concentrations and without toxicity to normal cells, resulting in a greater therapeutic index
compared with bortezomib, the current standard treatment
for multiple myeloma. In addition, DTP3 synergized with bortezomib and was effective in multiple myeloma cells that were
resistant to conventional treatments. Furthermore, DTP3 was
well tolerated, induced tumor shrinkage, and extended survival
in mouse models of multiple myeloma. These data identify
the GADD45β/MKK7 complex as a critical mediator of NFκBinduced survival and demonstrate a therapeutic strategy to
selectively inhibit NFκB signaling in cancer cells using DTP3. ■
Tornatore L, Sandomenico A, Raimondo D, Low C, Rocci A,
Tralau-Stewart C, et al. Cancer-selective targeting of the NFκB
survival pathway with GADD45β/MKK7 inhibitors. Cancer Cell
2014;26:495–508.
DECEMBER 2014CANCER DISCOVERY | 1365
Downloaded from cancerdiscovery.aacrjournals.org on April 28, 2017. © 2014 American Association for Cancer Research.
Published OnlineFirst November 6, 2014; DOI: 10.1158/2159-8290.CD-RW2014-231
Type I IFN Signaling in Cancer Cells Enhances Chemotherapy
Responses
Cancer Discovery 2014;4:1365. Published OnlineFirst November 6, 2014.
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Downloaded from cancerdiscovery.aacrjournals.org on April 28, 2017. © 2014 American Association for Cancer Research.