A novel B-RAF inhibitor blocks interleukin-8 (IL-8) synthesis in human melanoma xenografts, revealing IL-8 as a potential pharmacodynamic biomarker

Crawford, Shelby; Belajic, Daniel; Wei, Jianmei; Riley, Jason P.; Dunford, Paul J.; Bembenek, Scott D.; Fourie, Anne M.; Edwards, James P.; Karlsson, Lars; Brunmark, Anders; Wolin, Ronald; Blevitt, Jonathan M.

doi:10.1158/1535-7163.mct-07-0307

Cited by 26 publications

(21 citation statements)

References 34 publications

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“…As a consequence, in BCPAP cell lines, which express mutated BRAF V600E gene [18,19], other pathways, sustaining the high concentrations of CXCL8, are likely involved. This would be in line with the recent demonstration that high basal extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation, which characterizes cells harboring the BRAF V600E mutation is responsible for CXCL8 secretion [20]. The above evidences support the concept that the secretion of CXCL8 by thyroid tumor cells is dependent upon different pathways which i) would be switched on by specific genetic lesions; ii) would be more or less effective in enhancing the secretion of CXCL8.…”

Section: Discussionsupporting

confidence: 82%

“…Compounds with anti-BRAF kinase activity were successfully tested for their ability to block CXCL8 synthesis in melanoma cell lines harboring the BRAFV600E mutation [20]. In addition, besides type I and Type II interferons which were previously shown to inhibit the secretion of CXCL8 [13,15], other potentially interesting molecules to be tested for their CXCL8 inhibiting effects could include PPAR-c agonists.…”

Section: Discussionmentioning

confidence: 99%

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Normal human thyroid cells, BCPAP, and TPC-1 thyroid tumor cell lines display different profile in both basal and TNF-α-induced CXCL8 secretion

et al. 2015

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CXCL8 is secreted by both normal human thyrocytes (NHT) and thyroid cancer cell lines. CXCL8 displays several tumor-promoting effects and recent evidences indicate that its concentrations within the tumor microenvironment can impact the clinical course of the malignancy. Aim of this study was to compare the basal secretion of CXCL8 among NHT and thyroid cancer cell lines (TPC-1 and BCPAP), and to assess the specific cell response to TNF-α in terms of CXCL8 secretion. NHT primary cultures, TPC-1 and BCPAP cell lines were cultured with or without TNF-α (0, 0.1, 1, 10, and 100 ng/ml). CXCL8 levels were measured in the cell supernatants after 24 h. In basal condition, significant differences in the mean levels of CXCL8 were observed among the three cell types: NHT (110.5 ± 56.2 pg/ml), TPC1 (467.4 ± 43.2 pg/ml), and BCPAP (1731.8 ± 493.3 pg/ml), (F = 35.06; p < 0.0001). TNF-α significantly and in a dose-response manner induced CXCL8 secretion in NHT (F = 25.53; p < 0.00001), TPC-1 (F = 13.38; p < 0.0001), and BCPAP (F = 9.88; p < 0.001) cells. The magnitude of the TNF-α effect (fold-increase vs. basal level of CXCL8) differed significantly among the three cell types (F = 10.47; p < 0.0001). BCPAP were identified as the cells showing the highest basal secretion of CXCL8 and the less responsive to TNF-α. NHT, TPC-1, and BCPAP display significant differences in the secretion of both basal and TNF-α-induced CXCL8 secretion. These results indicate that the mechanisms regulating the secretion of CXCL8 differ in tumor cells harboring different genetic alterations suggesting that specific strategies aimed at inhibiting CXCL8 secretion will be required.

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Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Normal human thyroid cells, BCPAP, and TPC-1 thyroid tumor cell lines display different profile in both basal and TNF-α-induced CXCL8 secretion

et al. 2015

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“…Its production is known to be regulated by the RET receptor (38), and the inhibitory effect observed during sunitinib exposure is likely to be due, at least partly, to the inhibition of RET phosphorylation, as shown in Western blotting and siRNA experiments. Decreased tumor secretion of IL-8 during sunitinib treatment, observed both in vitro and in vivo, has been described in other carcinomas and can be due to other mechanisms including inhibition of VEGF regulatory loops (39). Furthermore, recent results indicated that IL-8 is highly expressed in some carcinomas (40) and could mediate sunitinib resistance in renal carcinoma (41).…”

Section: Discussionmentioning

confidence: 93%

Identification of Soluble Candidate Biomarkers of Therapeutic Response to Sunitinib in Medullary Thyroid Carcinoma in Preclinical Models

Broutin¹,

Ameur²,

Lacroix³

et al. 2011

Clinical Cancer Research

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Purpose: Medullary thyroid carcinoma (MTC), an aggressive rare tumor due to activating mutations in the proto-oncogene RET, requires new therapeutic strategies. Sunitinib, a potent inhibitor of RET, VEGF receptor (VEGFR)-1, VEGFR-2, VEGFR-3, and platelet-derived growth factor receptor (PDGFR)α/β, has been reported as clinically effective in some patients with advanced MTC. In this study, we examine molecular mechanisms of action of sunitinib and identify candidate soluble biomarkers of response. Experimental Design: Both in vitro and in vivo assays, using the human TT RETC634W MTC cell line, were done to assess the activity of sunitinib. Kinetic microarray studies were used to analyze molecular pathways modified by sunitinib and to identify candidate biomarkers that were subsequently investigated in the serum of patients. Results: Sunitinib displayed antiproliferative and antiangiogenic activities and inhibited RET autophosphorylation and activation of downstream signaling pathways. We showed that sunitinib treatment induced major changes in the expression of genes involved in tissue invasion and metastasis including vimentin (VIM), urokinase plasminogen (PLAU), tenascin-C (TN-C), SPARC, and CD44. Analyzing downregulated genes, we identified those encoding secreted proteins and, among them, interleukin (IL)-8 was found to be modulated in the serum of xenografted mice under sunitinib treatment. Furthermore, we demonstrated that metastatic MTC patients presented increased serum levels of IL-8 and TGF-β2. Conclusions: Experimental models confirm the clinical efficacy of sunitinib observed in a few studies. Molecular pathways revealed by genomic signatures underline the impact of sunitinib on tissue invasion. Selected soluble candidate biomarkers could be of value for monitoring sunitinib response in metastatic MTC patients. Clin Cancer Res; 17(7); 2044–54. ©2011 AACR.

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“…Interestingly, production of IL-8, which plays a role in the extravasation of melanoma cells by mediating ICAM-1 interaction with b2 integrin, was shown to be decreased following inhibition of BRAFV600E (29). Moreover, elevated plasma levels of IL-8 in mice bearing BRAFV600E melanoma xenografts were decreased by RAF inhibitor treatment (30). Our observation is consistent with these findings and, taken together, these findings suggest that reduction of IL-8 production may be important for prevention of metastasis in melanoma by RAF inhibitors and minimizing tumorigenic risk in nontarget tissues by MEK inhibitors.…”

Section: Discussionmentioning

confidence: 99%

Epithelial Tissue Hyperplasia Induced by the RAF Inhibitor PF-04880594 Is Attenuated by a Clinically Well-Tolerated Dose of the MEK Inhibitor PD-0325901

Torti¹,

Wojciechowicz²,

Hu³

et al. 2012

Molecular Cancer Therapeutics

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Clinical trials of selective RAF inhibitors in patients with melanoma tumors harboring activated BRAFV600E have produced very promising results, and a RAF inhibitor has been approved for treatment of advanced melanoma. However, about a third of patients developed resectable skin tumors during the course of trials. This is likely related to observations that RAF inhibitors activate extracellular signalregulated kinase (ERK) signaling, stimulate proliferation, and induce epithelial hyperplasia in preclinical models. Because these findings raise safety concerns about RAF inhibitor development, we further investigated the underlying mechanisms. We showed that the RAF inhibitor PF-04880594 induces ERK phosphorylation and RAF dimerization in those epithelial tissues that undergo hyperplasia. Hyperplasia and ERK hyperphosphorylation are prevented by treatment with the mitogen-activated protein/extracellular signal-regulated kinase (MEK) inhibitor PD-0325901 at exposures that extrapolate to clinically well-tolerated doses. To facilitate mechanistic and toxicologic studies, we developed a three-dimensional cell culture model of epithelial layering that recapitulated the RAF inhibitor-induced hyperplasia and reversal by MEK inhibitor in vitro. We also showed that PF-04880594 stimulates production of the inflammatory cytokine interleukin 8 in HL-60 cells, suggesting a possible mechanism for the skin flushing observed in dogs. The complete inhibition of hyperplasia by MEK inhibitor in epithelial tissues does not seem to reduce RAF inhibitor efficacy and, in fact, allows doubling of the PF-04880594 dose without toxicity usually associated with such doses. These findings indicated that combination treatment with MEK inhibitors might greatly increase the safety and therapeutic index of RAF inhibitors for the treatment of melanoma and other cancers.

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A novel B-RAF inhibitor blocks interleukin-8 (IL-8) synthesis in human melanoma xenografts, revealing IL-8 as a potential pharmacodynamic biomarker

Cited by 26 publications

References 34 publications

Normal human thyroid cells, BCPAP, and TPC-1 thyroid tumor cell lines display different profile in both basal and TNF-α-induced CXCL8 secretion

Normal human thyroid cells, BCPAP, and TPC-1 thyroid tumor cell lines display different profile in both basal and TNF-α-induced CXCL8 secretion

Identification of Soluble Candidate Biomarkers of Therapeutic Response to Sunitinib in Medullary Thyroid Carcinoma in Preclinical Models

Epithelial Tissue Hyperplasia Induced by the RAF Inhibitor PF-04880594 Is Attenuated by a Clinically Well-Tolerated Dose of the MEK Inhibitor PD-0325901

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