Chemotherapy Targeted Therapy

Published OnlineFirst October 23, 2014; DOI: 10.1158/2159-8290.CD-RW2014-218

RESEARCH WATCH

Chemotherapy

Major finding: The efficacy of anthra- Mechanism: Anthracyclines induce TLR3- Impact: High expression of a type I IFN cycline chemotherapy depends on acti- mediated type I IFN–IFNAR signaling and signature may predict successful an- vation of type I IFN immune responses. CXCL10 secretion by cancer cells. thracycline-based chemotherapy.

TYPE I IFN SIGNALING IN CANCER CELLS ENHANCES CHEMOTHERAPY RESPONSES Anthracyclines are effective chemotherapeutic agents that important role in antiviral and type I IFN immune responses, function in part by eliciting anticancer immune responses. Sis- by both mouse and human tumor cells. Blockade of CXCL10 tigu, Yamazaki, Vacchelli, and colleagues hypothesized that the signaling abrogated the antitumor effi cacy of doxorubicin, activity of anthracyclines may require type I IFN signaling, which whereas administration of recombinant CXCL10 was suffi cient is essential for the immune response to viral infections. Consist- to restore the sensitivity of IFNAR- and TLR-defi cient sarcoma ent with this idea, global transcriptome profi ling of murine cells to doxorubicin. Exogenous type I IFNs also enhanced the fi brosarcomas revealed that doxorubicin treatment increased sensitivity of tumor cells to cisplatin chemotherapy by stimulat- the expression of IFN-stimulated genes associated with viral ing protective IFNAR-mediated immune responses. Further- infection in neoplastic cells. Signaling of IFNαβ through the more, high expression of a type I IFN signature was predictive type I IFN receptor, IFNAR, in neoplastic but not host cells of pathologic complete response to neoadjuvant anthracycline- was required for the antitumor effects of anthracyclines. In based chemotherapy in patients with breast carcinoma and was addition, sarcomas defi cient in toll-like receptor 3 (TLR3), an associated with increased metastasis-free survival in patients endosomal pattern recognition receptor, failed to instigate a with poor prognosis. These data demonstrate that anthracy- type I IFN fi ngerprint following doxorubicin treatment and were clines mimic viral infection to induce optimal chemotherapeutic unable to respond to anthracycline-based chemotherapy, sug- responses and suggest that type I IFN signaling may represent a gesting that TLR3 activation by self-RNA released from dying useful clinical biomarker. ■ cells is necessary for anthracycline-induced production of type I IFNs. In response to anthracyclines, type I IFN–IFNAR signaling Sistigu A, Yamazaki T, Vacchelli E, Chaba K, Enot DP, Adam J, et al. stimulated autocrine and paracrine signaling and secretion of Cancer cell–autonomous contribution of type I interferon signaling to the chemokine (C-X-C motif) ligand 10 (CXCL10), which plays an effi cacy of chemotherapy. Nat Med 2014;20:1301–9.

Targeted Therapy

Major finding: GADD45β/MKK7 is criti- Mechanism: Disruption of the GADD45β/ Impact: Inhibition of GADD45β/MKK7 cal for NFκB-driven survival and is a MKK7 complex induces proapoptotic selectively blocks NFκB-mediated therapeutic target in multiple myeloma. JNK signaling in multiple myeloma cells. survival in certain cancer cells.

TARGETING GADD45b/MKK7 DOWNSTREAM OF NFkB INDUCES CANCER-SPECIFIC APOPTOSIS Many cancers, including multiple myeloma, specifi cally with MKK7 to activate JNK signaling exhibit aberrant activation of NFκB signaling, which and induce cancer-cell–specifi c apoptosis in a dose- promotes cancer-cell survival via the upregulation dependent manner. DTP3 also displayed potent and of antiapoptotic genes and renders cells sensitive selective activity in various cancer cell lines with to NFκB inhibition. However, to date, no NFκB- high GADD45B expression. Importantly, DTP3 was targeted therapies have been clinically approved due cytotoxic to primary myeloma cells from patients to toxicities associated with global NFκB inhibi- at low concentrations and without toxicity to nor- tion, underscoring the need to develop strategies mal cells, resulting in a greater therapeutic index to selectively inhibit cancer-specifi c NFκB signaling. Torna- compared with bortezomib, the current standard treatment tore and colleagues found that expression of the NFκB target for multiple myeloma. In addition, DTP3 synergized with bort- gene growth arrest and DNA-damage–inducible β (GADD45B), ezomib and was effective in multiple myeloma cells that were which encodes an inhibitor of the JNK kinase MKK7 (also resistant to conventional treatments. Furthermore, DTP3 was known as MAP2K7), was elevated in plasma cells from patients well tolerated, induced tumor shrinkage, and extended survival with multiple myeloma and was correlated with decreased in mouse models of multiple myeloma. These data identify survival. GADD45β was essential for NFκB-mediated survival the GADD45β/MKK7 complex as a critical mediator of NFκB- of multiple myeloma cells through inhibition of MKK7–JNK- induced survival and demonstrate a therapeutic strategy to driven apoptosis, suggesting GADD45β as a potential thera- selectively inhibit NFκB signaling in cancer cells using DTP3. ■ peutic target. A peptide library screen identifi ed two acetylated L-tetrapeptides that disrupted the GADD45β/MKK7 complex Tornatore L, Sandomenico A, Raimondo D, Low C, Rocci A, in vitro. Synthesis of the corresponding D-tetrapeptides and Tralau-Stewart C, et al. Cancer-selective targeting of the NFκB subsequent chemical optimization yielded DTP3, a highly sta- survival pathway with GADD45β/MKK7 inhibitors. Cancer Cell ble D-tripeptide with improved bioavailability that interacted 2014;26:495–508.

DECEMBER 2014CANCER DISCOVERY | 1365

Targeting GADD45β/MKK7 Downstream of NFκB Induces Cancer-Specific Apoptosis

Cancer Discovery 2014;4:1365. Published OnlineFirst October 23, 2014.

Updated version Access the most recent version of this article at: doi:10.1158/2159-8290.CD-RW2014-218

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