Augmentation of Therapeutic Responses in Melanoma by Inhibition of IRAK-1,-4

Srivastava, Ratika; Geng, Degui; Liu, Yingjia; Zheng, Luyao; Li, Zhaoyang; Joseph, Mary Ann; McKenna, Colleen; Bansal, Navneeta; Ochoa, Augusto C.; Dávila, Eduardo

doi:10.1158/0008-5472.can-12-0337

Cited by 69 publications

(59 citation statements)

References 24 publications

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“…We next investigated the phosphorylation status of IRAK4 (p-IRAK4) in 103 resected human PDAC samples by immunohistochemistry using a phospho-antibody that was previously reported in melanoma(27). We found p-IRAK4 to be present and significantly stronger in the ductal epithelia of 20 out of 30 (or 66.7%) PDAC samples (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Aside from PDAC, targeting the IRAK1/4 cascade has been shown to be a promising strategy in other malignancies including DLBCL(29, 40), myelodysplastic syndrome(41), T-cell ALL(42), melanoma(27), breast cancer(43), and head and neck cancer(44), further underscoring the urgent need to develop potent IRAK inhibitors for clinical testing. Another study showed that TAK1 inhibition could augment the effect of chemotherapy in PDAC(45).…”

Section: Discussionmentioning

confidence: 99%

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Constitutive IRAK4 Activation Underlies Poor Prognosis and Chemoresistance in Pancreatic Ductal Adenocarcinoma

Zhang

Jiang

et al. 2017

Clinical Cancer Research

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Purpose Aberrant activation of the NF-κB transcription factors underlies the aggressive behavior and poor outcome of pancreatic ductal adenocarcinoma (PDAC). However, clinically effective and safe NF-κB inhibitors are not yet available. Because NF-κB transcription factors can be activated by the Interleukin-1 Receptor-Associated Kinase (IRAK) downstream of the Toll-like receptors (TLRs), but has not been explored in PDAC, we sought to investigate the role of IRAK in the pathobiology of PDAC. Experimental Design We examined the phosphorylation status of IRAK4 (p-IRAK4), the master regulator of TLR signaling, in PDAC cell lines, in surgical samples and commercial tissue microarray. We then performed functional studies using small molecule IRAK1/4 inhibitor, RNA-interference and CRISPR/Cas9n techniques to delineate the role of IRAK4 in NF-κB activity, chemoresistance, cytokine production and growth of PDAC cells in vitro and in vivo. Results p-IRAK4 staining was detectable in the majority of PDAC lines and about 60% of human PDAC samples. Presence of p-IRAK4 strongly correlated with phospho-NF-κB/p65 staining in PDAC samples and is predictive of postoperative relapse and poor overall survival. Inhibition of IRAK4 potently reduced NF-κB activity, anchorage-independent growth, chemoresistance and secretion of pro-inflammatory cytokines from PDAC cells. Both pharmacologic suppression and genetic ablation of IRAK4 greatly abolished PDAC growth in mice and augmented the therapeutic effect of gemcitabine by promoting apoptosis, reducing tumor cell proliferation and tumor fibrosis. Conclusions Our data established IRAK4 as a novel therapeutic target for PDAC treatment. Development of potent IRAK4 inhibitors is needed for clinical testing.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Constitutive IRAK4 Activation Underlies Poor Prognosis and Chemoresistance in Pancreatic Ductal Adenocarcinoma

Zhang

Jiang

et al. 2017

Clinical Cancer Research

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“…Furthermore, it was reported that the IRAK1/4 inhibitor is effective in the treatment of melanoma [60] as well as myelodysplastic syndrome [61]. Since the IRAK family plays a key role in NF-κB signaling, IRAK2 may also be a therapeutic target for NSCLC.…”

Section: Discussionmentioning

confidence: 99%

Epigenetic silencing of microRNA-373 to epithelial-mesenchymal transition in non-small cell lung cancer through IRAK2 and LAMP1 axes

Seol¹,

Akiyama²,

Shimada³

et al. 2014

Cancer Letters

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The role of microRNAs (miRNAs) in carcinogenesis as tumor suppressors or oncogenes has been widely reported. Epigenetic change is one of the mechanisms of transcriptional silencing of miRNAs in cancer. To identify lung cancer-related miRNAs that are mediated by histone modification, we conducted microarray analysis in the Calu-6 non-small cell lung cancer (NSCLC) cell line after treatment with suberoylanilide hydroxamic acid (SAHA), a histone deacetylase (HDAC) inhibitor. The expression level of miR-373 was enhanced by SAHA treatment in this cell line by microarray and the following quantitative RT-PCR analyses. Treatment with another HDAC inhibitor, Trichostatin A, restored the levels of miR-373 expression in A549 and Calu-6 cells, while demethylation drug treatment did not. Importantly, miR-373 was found to be down-regulated in NSCLC tissues and cell lines. Transfection of miR-373 into A549 and Calu-6 cells attenuated cell proliferation, migration, and invasion and reduced the expression of mesenchymal markers. Additional microarray analysis of miR-373-transfected cells and computational predictions identified IRAK2 and LAMP1 as targets of miR-373. Knockdown of these two genes showed similar biological effects to those of miR-373 overexpression. In clinical samples, overexpression of IRAK2 correlated with decreased disease-free survival of patients with non-adenocarcinoma. In conclusion, we found that miR-373 is silenced by histone modification in lung cancer cells and identified its function as a tumor suppressor and negative regulator of the mesenchymal phenotype through downstream IRAK2 and LAMP1 target genes.

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“…Melanoma cells can express functional TLRs (17, 29). The Human Protein Atlas, an online immunohistochemistry (IHC) database evaluating the expression of various proteins and cancer types, shows TLR5 to be expressed at low levels on 30% of patients with melanoma.…”

Section: Resultsmentioning

confidence: 99%

TLR5 Ligand–Secreting T Cells Reshape the Tumor Microenvironment and Enhance Antitumor Activity

et al. 2015

Self Cite

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The tumor microenvironment counters antitumor T cell responses in part by blunting their activation and infiltration. Ligands that engage Toll-like receptors (TLR) on T cells and antigen-presenting cells can act as potent immune adjuvants. In this study, we show how tumor-reactive T cells engineered to secrete bacterial flagellin, a TLR5 ligand (TLR5L), can engender a co-stimulatory signal that augments antitumor activity. Human T cells engineered to express TLR5L along with DMF5, a T cell receptor that recognizes the melanoma antigen MART-127-35 (DMF5TLR5L T cells), displayed increased proliferation, cytokine production and cytolytic activity against melanoma cells. In a xenogenetic model, adoptive transfer of DMF5TLR5L T cells reduced tumor growth kinetics and prolonged mouse survival. In a syngeneic model, similarly engineered melanoma-reactive T cells (pmelTLR5L) displayed a relative increase in antitumor activity against established tumors, compared to unmodified T cells. In this model, we documented increased T cell infiltration associated with increased levels of CCR1 and CXCR3 levels on T cells, a reduction in PD1+Lag3+ T cells and CD11+Gr1+ myeloid-derived suppressor cells, and changes in the chemokine/cytokine profile of tumors. Our findings show how T cell-mediated delivery of a TLR agonist to the tumor site can contribute to antitumor efficacy, in the context of adoptive T cell immunotherapy.

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Augmentation of Therapeutic Responses in Melanoma by Inhibition of IRAK-1,-4

Cited by 69 publications

References 24 publications

Constitutive IRAK4 Activation Underlies Poor Prognosis and Chemoresistance in Pancreatic Ductal Adenocarcinoma

Constitutive IRAK4 Activation Underlies Poor Prognosis and Chemoresistance in Pancreatic Ductal Adenocarcinoma

Epigenetic silencing of microRNA-373 to epithelial-mesenchymal transition in non-small cell lung cancer through IRAK2 and LAMP1 axes

TLR5 Ligand–Secreting T Cells Reshape the Tumor Microenvironment and Enhance Antitumor Activity

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