Published OnlineFirst August 20, 2015; DOI: 10.1158/2159-8290.CD-RW2015-156 rEsEarch WATCH targeted therapy Major finding: Small-molecule blockade Mechanism: DEL-22379 inhibits ERK impact: Regulatory protein–protein of ERK dimerization delays tumorigenesis extranuclear activity and is not affected interactions represent potential driven by oncogenic RAS–ERK signaling. by drug-resistance mechanisms. therapeutic targets. inhibition of ErK dimErization impairs RAS–ErK-drivEn tumorigEnEsis Constitutive activation of the RAS–ERK pathway occurs of phosphoprotein enriched in astrocytes 15 (PEA15), which in nearly 50% of human cancers. Although several phar- retains ERK in the cytoplasm, correlated with levels of ERK macologic strategies to block this pathway have yielded dimerization and DEL-22379 sensitivity in BRAF-mutant positive results, long-lasting efficacy has been hampered by cells, supporting the idea that the antitumor activity of acquired resistance mutations that reactivate ERK signaling. DEL-22379 is dependent on ERK dimerization. Consistent As an alternative approach, Herrero and colleagues sought with this finding, DEL-22379 was ineffective in a RAS-driven to inhibit ERK dimerization, which specifically regulates the melanoma model in zebrafish, in which ERK does not dimer- extranuclear function of ERK and has been implicated in ize. Importantly, melanoma cells with NRAS overexpression tumorigenesis. Screening of small-molecule libraries identi- or MEK1 mutations remained sensitive to DEL-22379 treat- fied DEL-22379, which successfully blocked ERK dimeriza- ment, indicating that the antitumor activity of DEL-22379 is tion without affecting its phosphorylation; correspondingly, not affected by drug-resistance mechanisms associated with ERK cytoplasmic activity was significantly reduced, whereas existing inhibitors of the RAS–ERK pathway. Overall, these its nuclear functions were enhanced. Mutation of residues data describe a specific and effective treatment for RAS–ERK- within the dimerization interface of ERK disrupted the driven tumors and support the development of inhibitors of effects of DEL-22379, indicating that the compound binds regulatory protein–protein interactions, rather than catalytic directly to this interface and blocks dimer formation. DEL- activities, to prevent tumor progression. n 22379 inhibited growth and induced apoptosis in various tumor cell lines harboring mutant BRAF or RAS, whereas Herrero A, Pinto A, Colón-Bolea P, Casar B, Jones M, Agudo- wild-type cell lines were resistant. In vivo, DEL-22379 selec- Ibáñez L, et al. Small molecule inhibition of ERK dimerization tively inhibited the growth and metastasis of BRAF-mutant prevents tumorigenesis by RAS-ERK pathway oncogenes. Cancer Cell cell line–derived and patient-derived xenografts. Expression 2015;28:170–82. immunology Major finding: RORC1 promotes pro- Mechanism: RORC1 controls key tran- impact: Targeted inhibition of RORC1 tumorigenic innate immunity by stimu- scriptional regulators to induce expan- may prevent tumor growth and lating “emergency” myelopoiesis. sion of MDSCs and M2-polarized TAMs. metastasis. rorc1 drivEs cancEr-associatEd EmErgEncy myElopoiEsis The rapid change in hematopoietic output that tion of early hematopoietic progenitor cells in the occurs in response to acute immunologic stress is bone marrow into myeloid lineage cells in response known as “emergency” hematopoiesis, a process to colony-stimulating growth factors by inducing that is co-opted by tumors to enhance the gen- the expression of CCAAT/enhancer binding pro- eration of tumor-promoting myeloid cells. The tein β (C/EBPβ), a positive regulator of granulo- response of T-helper cells expressing IL17A, which poiesis, and inhibiting the expression of SOCS3 is controlled by retinoic acid–related orphan recep- and BCL3, negative regulators of granulopoiesis. tor C (RORC1), has been implicated in G-CSF– RORC1 regulated MDSC expansion by promoting mediated emergency myelopoiesis, prompting Strauss and CSF-mediated protection of immature MDSCs against apop- colleagues to investigate the role of the IL17A/RORC1 axis in tosis and suppressing neutrophil maturation, resulting in the cancer-related myeloid differentiation. Analysis of the myeloid survival of immature MDSCs. Concurrently, RORC1 enhanced compartment of tumor-bearing mice revealed that emergency the maturation of TAMs by inducing the lineage commitment hematopoiesis occurs early in tumor development and that transcription factors PU.1 and interferon regulatory factor 8 RORC1 expression in myeloid cells is indicative of advanced and promoted the M2 polarization of macrophages. Taken protumorigenic inflammation. Genetic deletion of Rorc1 in together, these results elucidate the role of RORC1 in the hematopoietic cells impaired tumor growth and metastasis regulation and coordination of tumor-promoting myeloid cell in multiple tumor models and resulted in a reduction in the expansion and differentiation and suggest targeted inhibition tumor-induced expansion of undifferentiated myeloid-derived of RORC1 as a potential therapeutic strategy. n suppressor cells (MDSC) and tumor-associated macrophages (TAM) compared with wild-type mice, supporting a role for Strauss L, Sangaletti S, Consonni FM, Szebeni G, Morlacchi S, RORC1 in promoting cancer-associated myelopoiesis. Further Totaro MG, et al. RORC1 regulates tumor-promoting “emergency” investigation revealed that RORC1 stimulated the differentia- granulo-monocytopoiesis. Cancer Cell 2015;28:253–69. 1014 | CANCER DISCOVERY OctOber 2015 www.aacrjournals.org Downloaded from cancerdiscovery.aacrjournals.org on October 2, 2021. © 2015 American Association for Cancer Research. CD-13-FM-Oct.indd 1014 17/09/15 10:50 AM Published OnlineFirst August 20, 2015; DOI: 10.1158/2159-8290.CD-RW2015-156 Inhibition of ERK Dimerization Impairs RAS−ERK-Driven Tumorigenesis Cancer Discovery 2015;5:1014. Published OnlineFirst August 20, 2015. Updated version Access the most recent version of this article at: doi:10.1158/2159-8290.CD-RW2015-156 E-mail alerts Sign up to receive free email-alerts related to this article or journal. Reprints and To order reprints of this article or to subscribe to the journal, contact the AACR Publications Subscriptions Department at [email protected]. Permissions To request permission to re-use all or part of this article, use this link http://cancerdiscovery.aacrjournals.org/content/5/10/1014.1. 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