Sorafenib induces paradoxical phosphorylation of the extracellular signal-regulated kinase pathway in acute myeloid leukemia cells lacking FLT3-ITD mutation

Fouladi, Fariba; Jehn, Lutz B.; Metzelder, Stephan; Hub, Florian; Henkenius, Katharina; Burchert, Andreas; Brendel, Cornelia; Stiewe, Thorsten; Neubauer, Andreas

doi:10.3109/10428194.2014.1003055

Cited by 6 publications

(6 citation statements)

References 29 publications

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“…Consistent with our data, earlier studies have also shown the inhibitory effect of sorafenib on ERK phosphorylation and proliferation of flt-3-mutant leukemia cells (14,15). Tyrosine kinase inhibitors, such as dasatinib and imatinib, have been shown to impede immune escape mechanisms in patients with CML by downregulation of MDSCs, simultaneously increasing T cell IFN-γ production (42).…”

Section: Discussionsupporting

confidence: 91%

“…Sorafenib is an inhibitor of several serine and threonine kinases, such as RAF, and tyrosine kinases, including VEGFRs. Sorafenib has been shown to block ERK activity and proliferation of flt-3-mutant acute myeloid leukemia cells (14,15) and reduce ERK phosphorylation of endothelial progenitor cells from patients with HCC (21). Activated ERK is a key downstream component of this signaling cascade that sorafenib is targeting.…”

Section: Discussionmentioning

confidence: 99%

“…ERK is a key molecule in the signaling cascade of Tregs and myeloid-derived suppressor cell (MDSC) activation, and signaling via Fms-related tyrosine kinase 3 (flt-3) has been shown to be vital for the proliferation and expansion of human Tregs (13). Recently, it has been reported that sorafenib inhibits ERK activation and proliferation of flt-3-mutant acute myeloid leukemia cells (14,15). We reasoned that ERK phosphorylation on flt-3 + Tregs and MDSCs could be central to understanding the immunomodulatory action of sorafenib, and we therefore measured the levels of ERK phosphorylation on flt-3 + Tregs and MDSCs of patients at the initiation of sorafenib treatment and multiple time points after treatment.…”

Section: L I N I C a L M E D I C I N Ementioning

confidence: 99%

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Augmentation of IFN-γ+ CD8+ T cell responses correlates with survival of HCC patients on sorafenib therapy

Kalathil¹,

Hutson²,

Barbi³

et al. 2019

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RESULTS. Elevated levels of CD8 + Ki67 + T cells producing IFN-γ were associated with improved progression-free survival and overall survival (OS). High frequencies of these T cells were correlated with significantly reduced risk of death over time. Patients with an increased pretreatment T effector/Treg ratio showed significant improvement in OS. ERK + flt-3 + Tregs and MDSCs were significantly decreased after sorafenib therapy. Increased numbers of baseline flt-3 + pERK + MDSCs were associated with survival benefit of patients. CONCLUSION. A high baseline CD4 + T effector/Treg ratio is a potential biomarker of prognostic significance in HCC. CD8 + Ki67 + T cells producing IFN-γ are a key biomarker of response to sorafenib therapy resulting in survival benefit. The immune modulation resulted from sorafenib-mediated blockade of signaling through the VEGF/VEGFR/flt-3 pathway, affecting ERK phosphorylation. These insights may help identify patients who likely would benefit from VEGFR antagonism and inform efforts to improve the efficacy of sorafenib in combination with immunotherapy. TRIAL REGISTRATION. NCT02072486.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: L I N I C a L M E D I C I N Ementioning

confidence: 99%

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Augmentation of IFN-γ+ CD8+ T cell responses correlates with survival of HCC patients on sorafenib therapy

Kalathil¹,

Hutson²,

Barbi³

et al. 2019

JCI Insight

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“…However, one should notice that 1 µM is a relatively low concentration for Sorafenib as the maximal plasma concentration of Sorafenib in patients reaches 10 to 21 µM [40–42]. Previous reports confirm that Sorafenib causes ERK paradoxical activation at low doses [43–45]. However, at higher doses (5 µM and 10 µM), Sorafenib caused ERK inhibition (Fig.…”

Section: Resultsmentioning

confidence: 96%

CRAF mutations in lung cancer can be oncogenic and predict sensitivity to combined type II RAF and MEK inhibition

et al. 2019

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Two out of 41 non-small cell lung cancer patients enrolled in a clinical study were found with a somatic CRAF mutation in their tumor, namely CRAFP261A and CRAFP207S. To our knowledge, both mutations are novel in lung cancer and CRAFP261A has not been previously reported in cancer. Expression of CRAFP261A in HEK293T cells and BEAS-2B lung epithelial cells led to increased ERK pathway activation in a dimer-dependent manner, accompanied with loss of CRAF phosphorylation at the negative regulatory S259 residue. Moreover, stable expression of CRAFP261A in mouse embryonic fibroblasts and BEAS-2B cells led to anchorage-independent growth. Consistent with a previous report, we could not observe a gain-of-function with CRAFP207S. Type II but not type I RAF inhibitors suppressed the CRAFP261A-induced ERK pathway activity in BEAS-2B cells, and combinatorial treatment with type II RAF inhibitors and a MEK inhibitor led to a stronger ERK pathway inhibition and growth arrest. Our findings suggest that the acquisition of a CRAFP261A mutation can provide oncogenic properties to cells, and that such cells are sensitive to combined MEK and type II RAF inhibitors. CRAF mutations should be diagnostically and therapeutically explored in lung and perhaps other cancers.

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“…However, the clinical efficacy of sorafenib was limited due to low sensitivity and high drug resistance ( 5 ). The first- and second-line drugs for advanced HCC require further development ( 6 ). Improving the efficacy of sorafenib has been popular in the discussion of HCC chemotherapy.…”

Section: Introductionmentioning

confidence: 99%

Silencing activating transcription factor 2 promotes the anticancer activity of sorafenib in hepatocellular carcinoma cells

et al. 2018

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The present study aimed to investigate the anticancer effect of sorafenib combined with silencing of activating transcription factor 2 (ATF2) in hepatocellular carcinoma (HCC) cells and to assess the underlying molecular mechanisms. Huh-7 HCC cell line was selected for the present study. Small interfering RNA (siRNA)-ATF2 sequence was constructed to silence ATF2 expression. The experiment was divided into 6 groups: i) Control; ii) vector; iii) sorafenib (6.8 µM); iv) vector+sorafenib; v) siRNA-ATF2; and vi) siRNA-ATF2+sorafenib groups. Cell proliferation, apoptosis, migration and invasion were detected following treatments with sorafenib and/or ATF2 silencing. Additionally, expression of tumor necrosis factor (TNF)-α and c-Jun N-terminal kinase 3 (JNK3) was detected using reverse transcription-quantitative polymerase chain reaction and western blotting. The current findings revealed that siRNA-ATF2 significantly reduced ATF2 expression. Cell proliferation, migration and invasion abilities in the sorafenib and siRNA-ATF2 groups were significantly reduced compared with the control group (P<0.05). Apoptotic rate in the sorafenib and siRNA-ATF2 groups was significantly increased compared with the control group (P<0.05). The mRNA and protein expression levels of ATF2 in the sorafenib or siRNA-ATF2 groups was significantly reduced when compared with control group. The phosphorylation of ATF2 was also reduced following sorafenib treatment or ATF2 silence. Although JNK3 mRNA expression level was not affected, the phosphorylation level of JNK3 was significantly promoted following sorafenib treatment or ATF2 silencing. Additionally, TNF-α mRNA and protein expression levels were increased following sorafenib treatment or ATF2 silencing. It is of note that siRNA-ATF2 treatment promoted the anticancer activity of sorafenib in Huh-7 cells. Additionally, siRNA-ATF2+sorafenib treatment combined additionally promoted TNF-α expression and phosphorylation of JNK3. Combined siRNA-ATF2 and sorafenib treatment had a greater anticancer effect compared with sorafenib or ATF2 silencing alone. The possible mechanism involved in the anticancer effect of sorafenib and ATF2 silencing may be associated with the activation of the TNF-α/JNK3 signaling pathway.

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Sorafenib induces paradoxical phosphorylation of the extracellular signal-regulated kinase pathway in acute myeloid leukemia cells lacking FLT3-ITD mutation

Cited by 6 publications

References 29 publications

Augmentation of IFN-γ+ CD8+ T cell responses correlates with survival of HCC patients on sorafenib therapy

Augmentation of IFN-γ+ CD8+ T cell responses correlates with survival of HCC patients on sorafenib therapy

CRAF mutations in lung cancer can be oncogenic and predict sensitivity to combined type II RAF and MEK inhibition

Silencing activating transcription factor 2 promotes the anticancer activity of sorafenib in hepatocellular carcinoma cells

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