Inhibition of ribonucleotide reductase (RNR), the rate-limiting enzyme in the synthesis of deoxyribonucleotides, causes DNA replication stress and activates the ataxia telangiectasia and rad3-related protein (ATR)-checkpoint kinase 1 (CHK1) pathway. Notably, a number of different cancers, including Ewing sarcoma tumors, are sensitive to the combination of RNR and ATR-CHK1 inhibitors. However, multiple, overlapping mechanisms are reported to underlie the toxicity of ATR-CHK1 inhibitors, both as single agents and in combination with RNR inhibitors, toward cancer cells. Here, we identified a feedback loop in Ewing sarcoma cells in which inhibition of the ATR-CHK1 pathway depletes RRM2, the small subunit of RNR, and exacerbates the DNA replication stress and DNA damage caused by RNR inhibitors. Mechanistically, we identified that the inhibition of ATR-CHK1 activates CDK2, which targets RRM2 for degradation via the proteasome. Similarly, activation of CDK2 by inhibition or knockdown of the WEE1 kinase also depletes RRM2 and causes DNA damage and apoptosis. Moreover, we show that the concurrent inhibition of ATR and WEE1 has a synergistic effect in Ewing sarcoma cells. Overall, our results provide novel insight into the response to DNA replication stress, as well as a rationale for targeting the ATR, CHK1, and WEE1 pathways, in Ewing sarcoma tumors. IMPLICATIONS: Targeting the ATR, CHK1, and WEE1 kinases in Ewing sarcoma cells activates CDK2 and increases DNA replication stress by promoting the proteasome-mediated degradation of RRM2.
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http://dx.doi.org/10.1158/1541-7786.MCR-19-0585 | DOI Listing |
Arch Orthop Trauma Surg
January 2025
Department of Orthopaedics and Trauma, Medical University of Graz, Auenbruggerplatz 5, 8036, Graz, Austria.
Introduction: Liquid biopsy as a non-invasive method to investigate cancer biology and monitor residual disease has gained significance in clinical practice over the years. Whilst its applicability in carcinomas is well established, the low incidence and heterogeneity of bone and soft tissue sarcomas explains the less well-established knowledge considering liquid biopsy in these highly malignant mesenchymal neoplasms.
Materials And Methods: A systematic literature review adhering to the PRISMA guidelines initially identified 920 studies, of whom 68 original articles could be finally included, all dealing with clinical applicability of liquid biopsy in sarcoma.
Cancers (Basel)
January 2025
Department of Thoracic Surgery, Ruhrlandklinik, University of Duisburg-Essen, 45239 Essen, Germany.
Objective: Ewing sarcoma (EWS) of the mediastinum is extremely rare, with only a few cases reported in the literature. We aimed to gain a better understanding of primary mediastinal EWS, describing patients treated within two international, multicenter, prospective, randomized EWS trials.
Methods: Data from patients with primary mediastinal EWS were retrieved from the database of the EURO-E.
Rare Tumors
January 2025
Internal Medicine Department, An Najah National University Hospital, Nablus, Palestine.
Ewing sarcoma family tumors (ESFT) pose diagnostic challenges, which largely depend on the primary site of involvement and tumor stage. Despite advancements in treatment, metastatic ESFTs remain associated with poor outcomes. This case describes a 21-year-old woman who, in July 2022, presented with a left breast mass identified through ultrasound and CT scan, along with abdominal distention.
View Article and Find Full Text PDFAnn Surg Oncol
January 2025
Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Introduction: Children and young adults diagnosed with sarcoma often present with pulmonary metastases requiring wedge resection. It is important to balance the risk of pulmonary recurrence against the desire to limit resection of benign parenchyma. This study aims to determine the impact of resection margins on survival and recurrence among pediatric and young adult sarcoma patients.
View Article and Find Full Text PDFJBJS Case Connect
January 2025
Morristown Medical Center, Morristown, New Jersey.
Case: We outline the management of a 10-month-old girl with an Ewing sarcoma involving the entire radius. The patient was treated with neoadjuvant chemotherapy resulting in almost a complete response. A limb-sparing procedure was performed consisting of a radical resection of the entire radius and centralization of the carpus to the ulna.
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