Targeting RRM2 and Mutant BRAF Is a Novel Combinatorial Strategy for Melanoma

Fatkhutdinov, Nail; Sproesser, Katrin; Krepler, Clemens; Liu, Qin; Brafford, Patricia; Herlyn, Meenhard; Aird, Katherine M.; Zhang, Rugang

doi:10.1158/1541-7786.mcr-16-0099

Cited by 29 publications

(26 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In previous work, we identified that Ewing sarcoma cells are sensitive to iron chelators and other drugs that inhibit RNR [ 21 ]. Inhibition of RNR is known to deplete nucleosides and cause DNA replication stress [ 32 – 34 ]. To test whether Ewing sarcoma cells are sensitive to DNA replication stress caused by mechanisms other than inhibition of RNR, we treated Ewing sarcoma and control cell lines with aphidicolin, which is an inhibitor of DNA polymerase α and δ and a drug that is frequently used to synchronize cells in S-phase [ 46 , 47 ].…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Inhibition of CHK1 sensitizes Ewing sarcoma cells to the ribonucleotide reductase inhibitor gemcitabine

et al. 2017

View full text Add to dashboard Cite

Ewing sarcoma is a bone and soft tissue sarcoma that occurs in children and young adults. The EWS-FLI1 gene fusion is the driver mutation in most Ewing sarcoma tumors and functions, in part, as an aberrant transcription factor. We recently identified that Ewing sarcoma cells are sensitive to inhibition of ribonucleotide reductase (RNR), which catalyzes the formation of deoxyribonucleotides from ribonucleotides. In this report, we show that Ewing sarcoma cells are sensitive to treatment with clofarabine, which is a nucleoside analogue and allosteric inhibitor of RNR. However, clofarabine is a reversible inhibitor of RNR and we found that the effect of clofarabine is limited when using a short (6-hour) drug treatment. Gemcitabine, on the other hand, is an irreversible inhibitor of the RRM1 subunit of RNR and this drug induces apoptosis in Ewing sarcoma cells when used in both 6-hour and longer drug treatments. Treatment of Ewing sarcoma cells with gemcitabine also results in activation of checkpoint kinase 1 (CHK1), which is a critical mediator of cell survival in the setting of impaired DNA replication. Notably, inhibition of CHK1 function in Ewing sarcoma cells using a small-molecule CHK1 inhibitor, or siRNA knockdown, in combination with gemcitabine results in increased toxicity both in vitro and in vivo in a mouse xenograft experiment. Overall, our results provide insight into Ewing sarcoma biology and identify a candidate therapeutic target, and drug combination, in Ewing sarcoma.

show abstract

Section: Resultsmentioning

confidence: 99%

“…Inhibition of RNR is known to cause cell cycle arrest and senescence in multiple types of cancer [ 32 – 34 ]. However, in Ewing sarcoma cells, in direct contrast to the other cell types we tested, inhibition of RNR causes cell cycle arrest and subsequent cell death with up-regulation of markers of apoptosis [ 21 ].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of CHK1 sensitizes Ewing sarcoma cells to the ribonucleotide reductase inhibitor gemcitabine

et al. 2017

View full text Add to dashboard Cite

show abstract

“…Nuclear accumulation of RRM2, which allows efficient DNA repair, is preceded by downregulation of cyclin F. As it has been shown by D'Angiolella et al the insertion of wild-type cyclin F into hTERT RPE-1 cells prevents transposition of RRM2 from the cytoplasm to the nucleus ( 5 ). It has also been shown that overexpression of RRM2 may affect the proliferation of melanoma cells, their response to treatment in vivo , and is associated with worse overall survival in melanoma patients bearing mutations in the BRAF oncogene ( 8 , 11 , 12 ). Based on these data, we hypothesized that low expression of cyclin F in melanoma patients can be related to a poorer prognosis.…”

Section: Discussionmentioning

confidence: 99%

“…Silencing of RRM2 inhibited melanoma growth which suggests the involvement of RRM2 in melanoma progression. Silencing of RRM2 and treatment with mutant BRAF inhibitor PLX4720 simultaneously and synergistically inhibited melanoma growth ( 11 ). It is possible that the negative effect of RRM2 overexpression is limited to patients bearing BRAF V600E mutation, but we cannot confirm this using TCGA data due to an insufficient number of patients with the BRAF mutation in the cohort.…”

Section: Discussionmentioning

confidence: 99%

Potential role of cyclin F mRNA expression in the survival of skin melanoma patients: Comprehensive analysis of the pathways altered due to cyclin F upregulation

et al. 2018

View full text Add to dashboard Cite

Cyclin F is a part of the Skp, Cullin, F-box containing ligase complex. The activity of cyclin F includes cell cycle control, centrosome duplication and response to DNA damage. The cyclin F expression pattern is very similar to cyclin A, but cyclin F is an orphan cyclin without its cyclin-dependent kinase partner. There is little evidence concerning the role of cyclin F in cancer. In the present study, for the first time, we present analysis from The Cancer Genome Atlas (TCGA) data in the context of expression of cyclin F mRNA in melanoma patients. Our original in silico analysis, not published elsewhere before, revealed that high expression of cyclin F in melanoma patients is associated with worse overall survival. Cyclin F and ribonucleotide reductase family member 2 (RRM2) compose a functional axis responsible for nucleotide metabolism. Impairment in this pathway may contribute to increased DNA damage repair and drug resistance. Additionally, we analyzed the expression of RRM2 mRNA and discovered that high expression of RRM2 is associated with worse overall survival. To shed more light on cyclin F overexpression in melanoma, we analyzed all protein data available in the TCGA melanoma dataset. It was found that in patients with upregulated cyclin F mRNA, we noted increased activity of pathways related to cell cycle and DNA damage repair. These data will support further in vitro and in vivo studies on the involvement of cyclin F in skin cutaneous melanoma.

show abstract

“…Recent data from HGSOC patients suggest that senescence occurs in vivo after therapy and is associated with a better outcome (46). Indeed, other publications have also indicated that senescence is a beneficial therapeutic response (47,48,(60)(61)(62)(63). The mechanism of senescence induction by the combination of ATM inhibition and fenofibrate remains to be explored.…”

Section: Discussionmentioning

confidence: 99%

ATM Inhibition Synergizes with Fenofibrate in High Grade Serous Ovarian Cancer Cells

Chen

Buj

Dahl

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

Background: Epithelial ovarian cancer (EOC) is the deadliest gynecological malignancy in the United States with high grade serous ovarian cancer (HGSOC) as the most commonly diagnosed subtype. While therapies targeting deficiencies in the homologous recombination (HR) pathway are emerging as the standard treatment for HGSOC patients, this strategy is limited to the 50% of patients with a deficiency in this pathway. Therefore, patients with HR-proficient tumors are likely to be resistant to these therapies and require alternative strategies. Methods:Data from HGSOC patients in The Cancer Genome Atlas (TCGA) were analyzed for ATM status, ATM and PPARa expression, and used to perform Gene Set Enrichment Analysis (GSEA). Screening data from the Dependency Map were analyzed to identify FDA-approved drugs that preferentially inhibit ATM-low cancer cells. In vitro studies were performed to determine whether ATM inhibitors synergize with the PPARa agonist fenofibrate in HGSOC cell lines. Results:The HR gene Ataxia Telangiectasia Mutated (ATM) is wildtype in the majority of HGSOC patients and its kinase activity is upregulated compared to normal fallopian tube tissue. As high ATM has been associated with poor overall and progression-free survival, targeting ATM may be beneficial for a subset of HGSOC patients. Clinical trials of ATM inhibitors are commencing; however, ATM inhibitors are not effective as single agents. We aimed to explore novel therapeutic vulnerabilities of ATM deficient cells to develop a combinatorial therapy. Using data from TCGA, we found that multiple pathways related to metabolism are inversely correlated with ATM expression, suggesting that combining ATM inhibition and metabolic inhibition would be effective. Indeed, analysis of FDA-approved drugs from the Dependency Map demonstrated that ATM low cell lines are more sensitive to fenofibrate, a PPARa agonist that has been previously shown to affect multiple cellular metabolic pathways. Consistently, PPARa signaling is associated with ATM expression. We validated that combined inhibition of ATM and treatment with fenofibrate is synergistic in multiple HGSOC cell lines by inducing senescence. Conclusions:Our results suggest that metabolic changes induced by ATM inhibitors are a potential target for the treatment for HGSOC.

show abstract

Targeting RRM2 and Mutant BRAF Is a Novel Combinatorial Strategy for Melanoma

Cited by 29 publications

References 51 publications

Inhibition of CHK1 sensitizes Ewing sarcoma cells to the ribonucleotide reductase inhibitor gemcitabine

Inhibition of CHK1 sensitizes Ewing sarcoma cells to the ribonucleotide reductase inhibitor gemcitabine

Potential role of cyclin F mRNA expression in the survival of skin melanoma patients: Comprehensive analysis of the pathways altered due to cyclin F upregulation

ATM Inhibition Synergizes with Fenofibrate in High Grade Serous Ovarian Cancer Cells

Contact Info

Product

Resources

About