MNK1/2 inhibition limits oncogenicity and metastasis of KIT-mutant melanoma

Yao, Zhan; Guo, Jun; Yang, William; Gonçalves, Christophe; Rzymski, Tomasz; Dreas, Agnieszka; Żyłkiewicz, Eliza; Mikulski, Maciej; Brzózka, Krzysztof; Gołas, Aniela; Kong, Yan; Ma, Meng; Fan, Huimin; Huor, Bonnie; Guo, Qian; Silva, Sabrina Daniela da; Torres, José; Cai, Yingying; Topisirović, Ivan; Su, Jie; Bijian, Krikor; Alaoui‐Jamali, Moulay A.; Huang, Sidong; Journé, Fabrice; Ghanem, Ghanem E.; Miller, Wilson H.; Rincón, Sonia V. del

doi:10.1172/jci91258

Cited by 65 publications

(66 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Representative polysome gradient profiles from MDMel-KI and MDMel-WT samples overlap ( Figure 3E), consistent with the role of phospho-eIF4E in regulating the translation of selective mRNAs, without exerting major effects on global protein synthesis 9,10,48,58 . Quantitative PCR analysis of RNA isolated from heavy and light polysome-bound fractions in MDMel-WT and MDMel-KI cells indicated that a lack of eIF4E phosphorylation leads to a redistribution of Ngfr mRNAs from heavy (efficiently translated) to light (poorly translated) polysomes ( Figure 3F).…”

Section: Ngfrsupporting

confidence: 69%

“…The MDMel-KI tumor derived cell lines, which are phospho-eIF4E deficient, failed to invade as efficiently as the MDMel-WT cells ( Figure 3B and Figure S3B), despite being more proliferative in vitro ( Figure S3C and S3D). Notably, previous studies by our group showed that the MKNK1/2 knockdown HBL cells are less invasive compared to their shCtrl counterparts, similar to the phospho-eIF4E-deficient MDMel-KI phenotype 48 .…”

Section: Ngfrmentioning

confidence: 60%

“…We next reasoned that blocking the activity of MNK1/2, the kinases that phosphorylate eIF4E, would reverse tumor cell plasticity in human melanoma cells. To test this, we used the invasive patient-derived melanoma cell line HBL wherein we previously knocked down MKNK1 and MKNK2 using shRNA 48 . MKNK1/2 knockdown in HBL cells showed reduced phospho-eIF4E level concomitant with increased pigmentation ( Figure 2F).…”

Section: Conversely Melanomas With Low Overall Phospho-eif4e Expressmentioning

confidence: 99%

See 2 more Smart Citations

The MNK1/2-eIF4E axis drives melanoma plasticity, progression, and resistance to immunotherapy

Fan

Gonçalves

Bartish

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

Melanomas commonly undergo a phenotype switch, from a proliferative to an invasive state. Melanoma plasticity exhibited as phenotype switching contributes to immunotherapy resistance, however the mechanisms are not completely understood and thus therapeutically unexploited. Here, using a transgenic melanoma mouse model, we demonstrated a critical role of the MNK1/2-eIF4E axis in melanoma plasticity and resistance to immunotherapy. We showed that phospho-eIF4E deficient murine melanomas express high levels of melanocytic antigens, with similar results verified in patient melanomas. Mechanistically, we identified that phospho-eIF4E controls the translation of NGFR, a critical effector of phenotype switching. In patients with melanoma, the expression of MKNK1, the kinase for eIF4E, positively correlated with markers of immune exhaustion. Genetic ablation of phospho-eIF4E reprogrammed the immunosuppressive microenvironment, exemplified by lowered production of inflammatory factors and increased CD8 + T cell infiltrates. Blocking phospho-eIF4E, using MNK1/2 inhibitors, offers a new strategy to inhibit melanoma plasticity and improve the survival response to anti-PD-1 immunotherapy.

show abstract

Section: Ngfrsupporting

confidence: 69%

Section: Ngfrmentioning

confidence: 60%

Section: Conversely Melanomas With Low Overall Phospho-eif4e Expressmentioning

confidence: 99%

See 1 more Smart Citation

The MNK1/2-eIF4E axis drives melanoma plasticity, progression, and resistance to immunotherapy

Fan

Gonçalves

Bartish

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…In skin cancer, melanoma is the most fatal due to its metastatic and aggressive characteristics. MNK1 activity is associated with invasion and metastasis in different types of melanoma, including KIT-mutant [104] and BRAFv6000Emutant melanoma [105]. The MNK1/2 inhibitor SEL201 inhibits invasion in both melanoma cells and in vivo melanoma models [102,104,105].…”

Section: Mnk In Other Solid Tumorsmentioning

confidence: 99%

“…MNK1 activity is associated with invasion and metastasis in different types of melanoma, including KIT-mutant [104] and BRAFv6000Emutant melanoma [105]. The MNK1/2 inhibitor SEL201 inhibits invasion in both melanoma cells and in vivo melanoma models [102,104,105]. Yang et al have demonstrated that MNK1 regulates melanoma metastasis through the upregulation of the angiopoietin-like 4 (ANGPTL4) protein, a regulator of MMPs, thus enabling the subsequent expression of MMPs that promote melanoma cell invasion [105].…”

Section: Mnk In Other Solid Tumorsmentioning

confidence: 99%

Deeping in the Role of the MAP-Kinases Interacting Kinases (MNKs) in Cancer

Pinto-Díez

Ferreras-Martín

Carrión-Marchante

et al. 2020

IJMS

View full text Add to dashboard Cite

The mitogen-activated protein kinase (MAPK)-interacting kinases (MNKs) are involved in oncogenic transformation and can promote metastasis and tumor progression. In human cells, there are four MNKs isoforms (MNK1a/b and MNK2a/b), derived from two genes by alternative splicing. These kinases play an important role controlling the expression of specific proteins involved in cell cycle, cell survival and cell motility via eukaryotic initiation factor 4E (eIF4E) regulation, but also through other substrates such as heterogeneous nuclear ribonucleoprotein A1, polypyrimidine tract-binding protein-associated splicing factor and Sprouty 2. In this review, we provide an overview of the role of MNK in human cancers, describing the studies conducted to date to elucidate the mechanism involved in the action of MNKs, as well as the development of MNK inhibitors in different hematological cancers and solid tumors.

show abstract

Comprehensive analysis of copy number variance and sensitivity to common targeted therapy in clear cell renal cell carcinoma: In silico analysis with in vitro validation

Shen

Zhang

et al. 2020

Cancer Medicine

View full text Add to dashboard Cite

The clear cell renal cell carcinoma (ccRCC) is in histopathology statistically accounting for more than 70% of renal cell carcinoma, which takes blame for diagnosis and deaths of 2% from all the carcinomas worldwide. 1 The tumorigenesis emerges firstly from renal tubular epithelial cell and grow as the similar morphology as that. Compared with the subtypes of collecting duct carcinoma and undifferentiated carcinoma, ccRCC shows an average malignancy. It has come to a consensus that the inactivation of VHL gene, a suppressor gene relevant with cellular oxygen sensing, does business for the

show abstract

MNK1/2 inhibition limits oncogenicity and metastasis of KIT-mutant melanoma

Cited by 65 publications

References 49 publications

The MNK1/2-eIF4E axis drives melanoma plasticity, progression, and resistance to immunotherapy

The MNK1/2-eIF4E axis drives melanoma plasticity, progression, and resistance to immunotherapy

Deeping in the Role of the MAP-Kinases Interacting Kinases (MNKs) in Cancer

Comprehensive analysis of copy number variance and sensitivity to common targeted therapy in clear cell renal cell carcinoma: In silico analysis with in vitro validation

Contact Info

Product

Resources

About