Targeting immunosuppression after standard sorafenib treatment to facilitate immune checkpoint blockade in hepatocellular carcinoma – an auto-commentary on clinical potential and future development

Chen, Yunching; Duda, Dan G.

doi:10.1080/2162402x.2015.1029703

Cited by 10 publications

(8 citation statements)

References 10 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Finally, we evaluated the treatment-induced changes in programmed death-1-ligand 1 (PD-L1) expression, an immune checkpoint which could suppress cytotoxic CD8+ T cell proliferation and activation, resulting in immunosuppression and treatment resistance 31 . We examined surgical specimens of HCC from patients with recurring tumors after sorafenib treatment and observed profound ERK activation and increased PD-L1 expression in recurrent HCC ( Figs S7 and S8 ).…”

Section: Resultsmentioning

confidence: 99%

Overcoming sorafenib evasion in hepatocellular carcinoma using CXCR4-targeted nanoparticles to co-deliver MEK-inhibitors

Chen

Liu

Sung

et al. 2017

Sci Rep

Self Cite

View full text Add to dashboard Cite

Sorafenib is a RAF inhibitor approved for several cancers, including hepatocellular carcinoma (HCC). Inhibition of RAF kinases can induce a dose-dependent “paradoxical” upregulation of the downstream mitogen-activated protein kinase (MAPK) pathway in cancer cells. It is unknown whether “paradoxical” ERK activation occurs after sorafenib therapy in HCC, and if so, if it impacts the therapeutic efficacy. Here, we demonstrate that RAF inhibition by sorafenib rapidly leads to RAF dimerization and ERK activation in HCCs, which contributes to treatment evasion. The transactivation of RAF dimers and ERK signaling promotes HCC cell survival, prevents apoptosis via downregulation of BIM and achieves immunosuppression by MAPK/NF-kB-dependent activation of PD-L1 gene expression. To overcome treatment evasion and reduce systemic effects, we developed CXCR4-targeted nanoparticles to co-deliver sorafenib with the MEK inhibitor AZD6244 in HCC. Using this approach, we preferentially and efficiently inactivated RAF/ERK, upregulated BIM and down-regulated PD-L1 expression in HCC, and facilitated intra-tumoral infiltration of cytotoxic CD8+ T cells. These effects resulted in a profound delay in tumor growth. Thus, this nano-delivery strategy to selectively target tumors and prevent the paradoxical ERK activation could increase the feasibility of dual RAF/MEK inhibition to overcome sorafenib treatment escape in HCC.

show abstract

Section: Resultsmentioning

confidence: 99%

Overcoming sorafenib evasion in hepatocellular carcinoma using CXCR4-targeted nanoparticles to co-deliver MEK-inhibitors

Chen

Liu

Sung

et al. 2017

Sci Rep

Self Cite

View full text Add to dashboard Cite

show abstract

“…On the other hand, our results indicate that treatment with 400 mg sorafenib twice daily might lead to immunosuppression and reduced anti‐tumour response by NK cells in vivo . This hypothesis can be strengthened by in‐vivo experiments in mouse models , while the clinical relevance of these findings remains unclear so far.…”

Section: Discussionmentioning

confidence: 99%

Sorafenib paradoxically activates the RAS/RAF/ERK pathway in polyclonal human NK cells during expansion and thereby enhances effector functions in a dose- and time-dependent manner

Lohmeyer

Nerreter

Dotterweich

et al. 2018

Clinical and Experimental Immunology

View full text Add to dashboard Cite

Natural killer (NK) cells play a major role in host immunity against leukaemia and lymphoma. However, clinical trials applying NK cells have not been as efficient as hoped for. Patients treated with rapidly accelerated fibrosarcoma (RAF) inhibitors exhibit increased tumour infiltration by immune cells, suggesting that a combination of RAF inhibitors with immunotherapy might be beneficial. As mitogen-activated protein kinases (MAPKs) such as raf-1 proto-oncogene, serine/threonine kinase (CRAF) regulate NK cell functions, we performed an in-vitro investigation on the potential of clinically relevant short-acting tyrosine kinase inhibitors (TKIs) as potential adjuvants for NK cell therapy: NK cells from healthy human blood donors were thus treated with sorafenib, sunitinib or the pan-RAF inhibitor ZM336372 during ex-vivo expansion. Functional outcomes assessed after washout of the drugs included cytokine production, degranulation, cytotoxicity, apoptosis induction and signal transduction with/without target cell contact. Paradoxically, sorafenib enhanced NK cell effector functions in a time- and dose-dependent manner by raising the steady-state activation level. Of note, this did not lead to NK cell exhaustion, but enhanced activity against target cells such as K562 or Daudis mediated via the RAS/RAF/extracellular-regulated kinase (ERK) pathway, but not via protein kinase B (AKT). Our data will pave the path to develop a rationale for the considered use of RAF inhibitors such as sorafenib for pre-activation in NK cell-based adoptive immune therapy.

show abstract

“…Furthermore, it does not interfere with chemotherapy on the level of tumor cells but increases the survival of cisplatin‐treated normal cells . With respect to immunotherapies, sorafenib might lead to an immunosuppressive phenotype, which could be reverted by immune checkpoint inhibition as shown for liver cell cancer . However, both EGFR and MET have been also shown to induce immune suppressive phenotypes, which might be attenuated by a treatment with sorafenib.…”

Section: Discussionmentioning

confidence: 99%

Receptor tyrosine kinase MET as potential target of multi‐kinase inhibitor and radiosensitizer sorafenib in HNSCC

et al. 2018

View full text Add to dashboard Cite

Background: The multi-kinase inhibitor sorafenib displays antitumoral effects in head and neck squamous cell carcinoma (HNSCC); however, the targeted kinases are unknown. Here we aimed to identify those kinases to determine the mechanism of sorafenib-mediated effects and establish candidate biomarkers for patient stratification. Methods: The effects of sorafenib and MET inhibitors crizotinib and SU11274 were analyzed using a slide-based antibody array, Western blotting, proliferation, and survival assays. X-rays were used for irradiations. Results: Sorafenib inhibited auto-phosphorylation of epidermal growth factor receptor and MET, which has not been described previously. MET expression in HNSCC cells was not always associated with activity/phosphorylation. Furthermore, sorafenib-dependent cell kill and radiosensitization was not associated with MET level. Although MET inhibitors blocked proliferation, they caused only mild cytotoxicity and no radiosensitization. Conclusion: We identified MET as a new potential target of sorafenib. However, MET inhibition is not the cause for sorafenib-mediated cytotoxicity or radiosensitization.

show abstract

Targeting immunosuppression after standard sorafenib treatment to facilitate immune checkpoint blockade in hepatocellular carcinoma – an auto-commentary on clinical potential and future development

Cited by 10 publications

References 10 publications

Overcoming sorafenib evasion in hepatocellular carcinoma using CXCR4-targeted nanoparticles to co-deliver MEK-inhibitors

Overcoming sorafenib evasion in hepatocellular carcinoma using CXCR4-targeted nanoparticles to co-deliver MEK-inhibitors

Sorafenib paradoxically activates the RAS/RAF/ERK pathway in polyclonal human NK cells during expansion and thereby enhances effector functions in a dose- and time-dependent manner

Receptor tyrosine kinase MET as potential target of multi‐kinase inhibitor and radiosensitizer sorafenib in HNSCC

Contact Info

Product

Resources

About