Correlation of ERK-phosphorylation and toxicities in patients treated with the Raf kinase inhibitor BAY 43-9006

Ra, Hilger; Kredtke, S; Me, Scheulen; Seeber, S.; Strumberg, Dirk

doi:10.5414/cpp42648

Cited by 9 publications

(9 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We found that exposure to pharmacologic concentrations of sunitinib 9,11,16,26 did not modify the phenotype of immature or mature MDDCs ( Figure 1A,B). However, immature DCs exposed to sorafenib exhibited a pronounced down-regulation of CD1a, CD86, and the integrin DC-SIGN, a C-type lectin that mediates adhesion to T cells by stabilizing the DC/T cells' contact zone ( Figure 1C).…”

Section: Exposure Of Immature Dcs To Sorafenib Inhibits Their Activatmentioning

confidence: 87%

“…It is known that PBLs isolated from patients receiving clinically relevant doses of sorafenib show inhibition of ERK phosphorylation on ex vivo PMA stimulation. 16 We therefore analyzed the immunomodulatory functions of these compounds using T cells and monocyte-derived dendritic cells (MDDCs), which were activated with ligands for TLR3 or 4. We found that sorafenib, but not sunitinib, has a detrimental effect on DC phenotype and inhibits cytokine secretion, migration ability, and T-cell stimulatory capacity, whereas the function and phenotype of T cells were not affected.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Sorafenib, but not sunitinib, affects function of dendritic cells and induction of primary immune responses

Hipp

Hilf

Walter

et al. 2008

Blood

262

232

View full text Add to dashboard Cite

IntroductionMetastatic renal cell cancer (RCC) has a very poor prognosis with a median survival of only 6 to 12 months from the time of diagnosis. 1,2 Historically, there were no established effective treatment approaches for metastatic RCC because of its resistance to radiation and chemotherapy. 3 Until recently, cytokine-based immunotherapy using interferon-␣ (IFN-␣) and/or interleukin-2 (IL-2) was the only effective treatment resulting in response rates of 10% to 20%. 4 The understanding of RCC pathogenesis and identification of molecular mechanisms responsible for the malignant transformation and metastatic spread led to the development of drugs that target cancer-specific pathways, such as the PI3K/AKT and Ras/Raf/MAPK pathways. 5 RCC is often associated with up-regulated Raf1, EGFR, and VEGFR activity. 5,6 Furthermore, in a high proportion of RCC, mutational aberrations of the von Hippel-Lindau (VHL) gene were identified. The loss-of-function of this tumor suppressor gene results in an accumulation of hypoxia inducible factor (HIF)-␣ subunits and stimulation of angiogenesis via VEGF-and PDGF-receptors.Consequently, 2 novel tyrosine kinase inhibitors, sorafenib (Bayer HealthCare, Leverkusen, Germany) 5 and sunitinib (Pfizer, New York, NY), were introduced in the treatment of RCC patients.Sorafenib is a multikinase inhibitor initially developed to inhibit the Raf1-kinase pathway. 2 However, besides the RAF/MEK/ERK pathway, sorafenib targets receptor tyrosine kinases (RTKs), such as VEGFR-2 and -3, PDGFR-␤, Flt-3, and c-KIT. 2,7 In several clinical and preclinical trials, sorafenib was revealed to be a promising anticancer therapeutic, which negatively regulates tumor growth, cell proliferation, and angiogenesis 8,9 and additionally induces apoptosis in tumor cells. 10 In December 2005, sorafenib was approved by the FDA for treatment of patients with advanced/ metastatic RCC. In a randomized trial, sorafenib doubled the median duration of progression-free survival up to 24 weeks in patients refractory to or relapsed during cytokine treatment. 2,11,12 Sunitinib inhibits multiple split kinase domain RTKs, including VEGFR-1 and -2, PDGFR-␣ and -␤, c- 7,13 In 2 phase 2 studies, application of sunitinib resulted in response rates up to 40% and in a randomized phase 3 trial it showed an improved response rate and progression-free survival in comparison to 14,15 However, until now the effects of sorafenib and sunitinib on development and function of normal nonmalignant hematopoetic cells have not been evaluated in detail. It is known that PBLs isolated from patients receiving clinically relevant doses of sorafenib show inhibition of ERK phosphorylation on ex vivo PMA stimulation. 16 We therefore analyzed the immunomodulatory functions of these compounds using T cells and monocyte-derived dendritic cells (MDDCs), which were activated with ligands for TLR3 or 4. We found that sorafenib, but not sunitinib, has a detrimental effect on DC phenotype and inhibits cytokine secretion, migration ability, and T-cell stimulator...

show abstract

Section: Exposure Of Immature Dcs To Sorafenib Inhibits Their Activatmentioning

confidence: 87%

mentioning

confidence: 99%

Sorafenib, but not sunitinib, affects function of dendritic cells and induction of primary immune responses

Hipp

Hilf

Walter

et al. 2008

Blood

262

232

View full text Add to dashboard Cite

show abstract

“…Substantial inhibition of PMA-stimulated ERK phosphorylation in peripheral blood lymphocytes (PBLs) from the treated patients was observed. The time course and extent of ERK inhibition in PBLs tended to parallel the dose level of BAY 43-9006 administered [49]. Clinical studies with BAY 43-9006 in combination with other chemotherapy agents are in progress.…”

Section: Inhibitors Of the Raf Protein Kinasesmentioning

confidence: 99%

“…The utility of these assays in phase I studies was demonstrated for the MEK inhibitor CI-1040 [83] and for the Raf kinase inhibitor BAY 43-9006 [49,60]. Regarding clinical studies, biomarker evaluation of phosphorylated ERK levels can also be measured in PMA-stimulated peripheral blood mononuclear cells [49,60]. Such assays have the potential to define a dose threshold that delivers total suppression of the desired target.…”

Section: Pharmacodynamic Evaluation Of Inhibition Of the Ras-raf-mek-mentioning

confidence: 99%

“…Likewise, phospho-specific antibodies specific for ERK1/2 can also be used for estimation of Raf kinase inhibition since ERK1/2 can only be activated by MEK [55]. The utility of these assays in phase I studies was demonstrated for the MEK inhibitor CI-1040 [83] and for the Raf kinase inhibitor BAY 43-9006 [49,60]. Regarding clinical studies, biomarker evaluation of phosphorylated ERK levels can also be measured in PMA-stimulated peripheral blood mononuclear cells [49,60].…”

Section: Pharmacodynamic Evaluation Of Inhibition Of the Ras-raf-mek-mentioning

confidence: 99%

See 1 more Smart Citation

The Ras-Raf-MEK-ERK Pathway in the Treatment of Cancer

Hilger¹,

Scheulen²,

Strumberg³

2002

Oncol Res Treat

Self Cite

215

169

View full text Add to dashboard Cite

The mitogen activated protein kinases (MAPKs) are conserved proteins that regulate cell growth, division and death. Although activated in the cytosol, the MAPKs translocate to the nucleus upon activation and phosphorylate a large number of nuclear proteins. Investigating how Ras transmits extracellular growth signals, the MAPK pathway has emerged as the crucial route between membrane-bound Ras and the nucleus. The MAPK pathway represents a cascade of phosphorylation events including three pivotal kinases, namely Raf, MEK (MAP kinase kinase), and ERK (MAP kinase). These kinases present new opportunities for the development of novel anti-cancer drugs designed to be target-specific and probably less toxic than conventional chemotherapeutic agents. A number of drugs inhibiting Ras, Raf or MEK are currently under clinical investigation. This review addresses the rationale for targeting the MAP kinase pathway and the current status of various pharmacological approaches.

show abstract

Inhibition of Growth Factor Signaling by Small-Molecule Inhibitors of ErbB, Raf, and MEK

Wallace

Yeh

Laird

et al. 2006

Topics in Medicinal Chemistry

View full text Add to dashboard Cite

Correlation of ERK-phosphorylation and toxicities in patients treated with the Raf kinase inhibitor BAY 43-9006

Cited by 9 publications

References 0 publications

Sorafenib, but not sunitinib, affects function of dendritic cells and induction of primary immune responses

Sorafenib, but not sunitinib, affects function of dendritic cells and induction of primary immune responses

The Ras-Raf-MEK-ERK Pathway in the Treatment of Cancer

Inhibition of Growth Factor Signaling by Small-Molecule Inhibitors of ErbB, Raf, and MEK

Contact Info

Product

Resources

About