Three-Dimensionally-Printed Joint-Preserving Prosthetic Reconstruction of Massive Bone Defects After Malignant Tumor Resection of the Proximal Tibia

Gürsan, Onur; Celtik, Mustafa; Yanik, Berkay; Hüsemoğlu, R. Buğra; Havıtçıoğlu, Hasan

doi:10.7759/cureus.13784

Cited by 2 publications

(1 citation statement)

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“…Ewing sarcoma is an aggressive childhood malignancy that typically presents in the bone (1). Over the past several decades, many of the advances in treatment have come in the form of technological progress, such as the development of novel prosthetics that have enabled an expansion of the number of patients that qualify for surgical resection of primary tumors (2)(3)(4). Significant advancements to chemotherapy regimens have been incremental, with most changes affecting treatment intervals and durations (5).…”

Section: Introductionmentioning

confidence: 99%

WEE1 Inhibition Augments CDC7 (DDK) Inhibitor–induced Cell Death in Ewing Sarcoma by Forcing Premature Mitotic Entry and Mitotic Catastrophe

Martin

Sims

Gupta

et al. 2022

Cancer Research Communications

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Ewing sarcoma is an aggressive childhood cancer for which treatment options remain limited and toxic. There is an urgent need for the identification of novel therapeutic strategies. Our group has recently shown that Ewing cells rely on the S-phase kinase CDC7 (DDK) to maintain replication rates and cell viability and that DDK inhibition causes an increase in the phosphorylation of CDK1 and a significant delay in mitotic entry. Here, we expand on our previous findings and show that DDK inhibitor-induced mitotic entry delay is dependent upon WEE1 kinase. Specifically, WEE1 phosphorylates CDK1 and prevents mitotic entry upon DDK inhibition due to the presence of under-replicated DNA, potentially limiting the cytotoxic effects of DDK inhibition. To overcome this, we combined the inhibition of DDK with the inhibition of WEE1 and found that this results in elevated levels of premature mitotic entry, mitotic catastrophe, and apoptosis. Importantly, we have found that DDK and WEE1 inhibitors display a synergistic relationship with regards to reducing cell viability of Ewing sarcoma cells. Interestingly, the cytotoxic nature of this combination can be suppressed by the inhibition of CDK1 or microtubule polymerization, indicating that mitotic progression is required to elicit the cytotoxic effects. This is the first study to display the potential of utilizing the combined inhibition of DDK and WEE1 for the treatment of cancer. We believe this will offer a potential therapeutic strategy for the treatment of Ewing sarcoma as well as other tumor types that display sensitivity to DDK inhibitors.

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