Targeting Radiation-Induced G2 Checkpoint Activation with the Wee-1 Inhibitor MK-1775 in Glioblastoma Cell Lines

Sarcar, Bhaswati; Kahali, Soumen; Prabhu, Antony; Shumway, Stuart D.; Xu, Yang; Demuth, Tim; Chinnaiyan, Prakash

doi:10.1158/1535-7163.mct-11-0469

Cited by 95 publications

(93 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Previous studies have demonstrated the efficacy of inhibiting Wee1 in combination with DNA damaging agents, such as gemcitabine (39–42) in the context of non-functional P53. MK-1775 monotherapy has been previously documented by Kreahling et al (30) where tumor explants treated with 500 nM MK-1775 for 24 hours demonstrated decreased CDK1 phosphorylation and features of cell death.…”

Section: Discussionmentioning

confidence: 99%

Quantitative Phosphoproteomics Reveals Wee1 Kinase as a Therapeutic Target in a Model of Proneural Glioblastoma

et al. 2016

View full text Add to dashboard Cite

Glioblastoma (GBM) is the most common malignant primary brain cancer. With a median survival of about a year, new approaches to treating this disease are necessary. To identify signaling molecules regulating GBM progression in a genetically engineered murine model of proneural GBM, we quantified phosphotyrosine mediated signaling using mass spectrometry. Oncogenic signals, including phosphorylated ERK MAPK, PI3K, and PDGFR, were found to be increased in the murine tumors relative to brain. Phosphorylation of CDK1 pY15, associated with the G2 arrest checkpoint, was identified as the most differentially phosphorylated site, with a 14-fold increase in phosphorylation in the tumors. To assess the role of this checkpoint as a potential therapeutic target, syngeneic primary cell lines derived from these tumors were treated with MK-1775, an inhibitor of Wee1, the kinase responsible for CDK1 Y15 phosphorylation. MK-1775 treatment led to mitotic catastrophe, as defined by increased DNA damage and cell death by apoptosis. To assess the extensibility of targeting Wee1/CDK1 in GBM, patient-derived xenograft (PDX) cell lines were also treated with MK-1775. Although the response was more heterogeneous, on-target Wee1 inhibition led to decreased CDK1 Y15 phosphorylation and increased DNA damage and apoptosis in each line. These results were also validated in vivo, where single-agent MK-1775 demonstrated an anti-tumor effect on a flank PDX tumor model, increasing mouse survival by 1.74-fold. This study highlights the ability of unbiased quantitative phosphoproteomics to reveal therapeutic targets in tumor models, and the potential for Wee1 inhibition as a treatment approach in pre-clinical models of GBM.

show abstract

Section: Discussionmentioning

confidence: 99%

Quantitative Phosphoproteomics Reveals Wee1 Kinase as a Therapeutic Target in a Model of Proneural Glioblastoma

et al. 2016

View full text Add to dashboard Cite

show abstract

“…1B). MLN4924 also induced accumulation of p21, p27, inhibitor of G 2 -M phase transition Wee1 (26) and an increase in cyclin B, accompanied by a decrease in the level of phosphohistone H3 (p-H3), a hallmark of M-phase cells (27), indicating that MLN4924-treated cells were arrested at the G 2 phase (Fig. 1C).…”

Section: Neddylation Inhibition With Mln4924 Triggered G 2 Cell Cyclementioning

confidence: 92%

Neddylation inhibitor MLN4924 induces G2 cell cycle arrest, DNA damage and sensitizes esophageal squamous cell carcinoma cells to cisplatin

Lin

Shang

et al. 2017

Oncol Lett

View full text Add to dashboard Cite

Abstract. Inhibiting the protein neddylation pathway using the NEDD8-activating enzyme inhibitor MLN4924 represents an attractive anticancer strategy having been demonstrated to exhibit promising anticancer efficacy and with tolerable levels of toxicity; however, the mechanism by which MLN4924 inhibits cell proliferation in human esophageal squamous cell carcinoma (ESCC) cells requires further investigation. The present study revealed that MLN4924 treatment led to G 2 cell cycle arrest and enhanced the protein stability of Wee1-like protein kinase and cyclin dependent protein kinase inhibitor 1A and B and p27. Furthermore, MLN4924 induced DNA damage and sensitized esophageal cancer cells to cisplatin by enhancing apoptosis. These findings extend the understanding of the function and mechanism of MLN4924 in ESCC and provide further evidence for the future development of neddylation inhibitors in clinical trials of esophageal cancer therapy, either alone or in combination.

show abstract

“…To determine at which phase MLN4924-treated cells were arrested, we detected the expression status of Wee1, a welldefined CRL/SCF substrate and an inhibitor of G 2 -M phase transition (35), as well as p-Histone H3 (p-H3, ser10), a hallmark of M phase cells (36). As shown in Fig.…”

Section: Mln4924 Induced G 2 Cell-cycle Arrest and Apoptosis In Livermentioning

confidence: 99%

The Nedd8-Activating Enzyme Inhibitor MLN4924 Induces Autophagy and Apoptosis to Suppress Liver Cancer Cell Growth

Luo

Lee³

et al. 2012

Cancer Research

205

204

View full text Add to dashboard Cite

Posttranslational neddylation of cullins in the Cullin-Ring E3 ligase (CRL) complexes is needed for proteolytic degradation of CRL substrates, whose accumulation induces cell-cycle arrest, apoptosis, and senescence. The Nedd8-activating enzyme (NAE) is critical for neddylation of CRL complexes and their growth-promoting function. Recently, the anticancer small molecule MLN4924 currently in phase I trials was determined to be an inhibitor of NAE that blocks cullin neddylation and inactivates CRL, triggering an accumulation of CRL substrates that trigger cell-cycle arrest, apoptosis, and senescence in cancer cells. Here, we report that MLN4924 also triggers autophagy in response to CRL inactivation and that this effect is important for the ability of MLN4924 to suppress the outgrowth of liver cancer cells in vitro and in vivo. MLN4924-induced autophagy was attributed partially to inhibition of mTOR activity, due to accumulation of the mTOR inhibitory protein Deptor, as well as to induction of reactive oxygen species stress. Inhibiting autophagy enhanced MLN4924-induced apoptosis, suggesting that autophagy is a survival signal triggered in response to CRL inactivation. In a xenograft model of human liver cancer, MLN4924 was well-tolerated and displayed a significant antitumor effect characterized by CRL inactivation and induction of autophagy and apoptosis in liver cancer cells. Together, our findings support the clinical investigation of MLN4924 for liver cancer treatment and provide a preclinical proof-of-concept for combination therapy with an autophagy inhibitor to enhance therapeutic efficacy. Cancer Res; 72(13); 3360-71. Ó2012 AACR.

show abstract

Targeting Radiation-Induced G2 Checkpoint Activation with the Wee-1 Inhibitor MK-1775 in Glioblastoma Cell Lines

Cited by 95 publications

References 20 publications

Quantitative Phosphoproteomics Reveals Wee1 Kinase as a Therapeutic Target in a Model of Proneural Glioblastoma

Quantitative Phosphoproteomics Reveals Wee1 Kinase as a Therapeutic Target in a Model of Proneural Glioblastoma

Neddylation inhibitor MLN4924 induces G2 cell cycle arrest, DNA damage and sensitizes esophageal squamous cell carcinoma cells to cisplatin

The Nedd8-Activating Enzyme Inhibitor MLN4924 Induces Autophagy and Apoptosis to Suppress Liver Cancer Cell Growth

Contact Info

Product

Resources

About