[Corrigendum] WEE1 inhibition by MK1775 as a single‑agent therapy inhibits ovarian cancer viability

Zhang, Minghui; Dominguez, Donye; Chen, Siqi; Fan, Jia; Qin, Lei; Long, Alan; Li, Xia; Zhang, Yi; Shi, Huirong; Zhang, Bin

doi:10.3892/ol.2018.8757

Cited by 16 publications

(3 citation statements)

References 38 publications

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“…Since CIC-DUX4 transcriptionally upregulates CCNE1, which can induce a high replicative stress state in cancer (5,6,(9)(10)(11)23), we hypothesized that WEE1 activity in CIC-DUX4 sarcomas may be an adaptive survival mechanism. To test whether WEE1 is necessary for CIC-DUX4 survival, we treated two independent patient-derived CIC-DUX4 cell lines (NCC_CDS1_X1_C1 and NCC_CDS2_C1) (22, 24) with the WEE1 inhibitor, adavosertib (AZD1775) (25)(26)(27)(28). Adavosertib treatment significantly decreased viability of both NCC_CDS1_X1_C1 and NCC_CDS2_C1 cells as measured by Cell-Titer Glo (CTG) and crystal violet assays (Figure 2A-C).…”

Section: Resultsmentioning

confidence: 99%

“…Future studies should focus on rational combinatorial strategies to enhance DNA damage and potentially augment WEE1 inhibitor responses. Adavosertib is currently being evaluated in multiple tumor histologies and is proven safe as monotherapy or in combination with other conventional targeted and chemotherapy agents as well as radiotherapy (11, 27, 28, 37). Thus, adavosertib therapy is potentially a safe and efficacious therapy (28) that can be rapidly employed in the clinic to more effectively target CIC-DUX4 sarcomas.…”

Section: Resultsmentioning

confidence: 99%

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WEE1 kinase is a therapeutic vulnerability in CIC-DUX4 undifferentiated sarcoma

et al. 2021

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CIC-DUX4 rearrangements define an aggressive and chemotherapy-insensitive subset of undifferentiated sarcomas. The CIC-DUX4 fusion drives oncogenesis through direct transcriptional upregulation of cell cycle and DNA replication genes. Notably, CIC-DUX4-mediated CCNE1 upregulation compromises the G1/S transition, conferring a potential survival dependence on the G2/M cell cycle checkpoint. Through an integrative transcriptional and kinase activity screen using patient-derived specimens, we now show that CIC-DUX4 sarcomas depend on the G2/M checkpoint regulator, WEE1, as an adaptive survival mechanism. Specifically, CIC-DUX4 sarcomas depend on WEE1 activity to limit DNA damage and unscheduled mitotic entry. Consequently, genetic or pharmacologic WEE1 inhibition in vitro and in vivo leads to rapid DNA damage-associated apoptotic induction of patient-derived CIC-DUX4 sarcomas. Thus, we identify WEE1 as an actionable therapeutic vulnerability in CIC-DUX4 sarcomas.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

WEE1 kinase is a therapeutic vulnerability in CIC-DUX4 undifferentiated sarcoma

et al. 2021

Preprint

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“…This work is the first to shed light on the kinase Wee1’s carcinogenic significance and regulatory mechanism of DDR in CML. Although Wee1 has been previously reported to be an oncogenic factor [ 19 – 22 ], and suppressing Wee1 exerted an anticancer effect in ovarian cancer [ 35 ] and osteosarcoma cells [ 36 ], whereas in CML, on the other hand, Wee1’s engagement related with DRR has never been extensively illustrated. We reported Wee1’s consistently overexpressed in CML cells when compared to controls cells.…”

Section: Discussionmentioning

confidence: 99%

Wee1 promotes cell proliferation and imatinib resistance in chronic myeloid leukemia via regulating DNA damage repair dependent on ATM-γH2AX-MDC1

et al. 2022

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Background The treatment of chronic myeloid leukemia (CML) is facing the dilemma of tyrosine kinase inhibitors (TKIs) resistance and disease recurrence. The dysfunctional DNA damage repair mechanism plays an essential role not only in the initiation and progression of hematological malignancies but also links to the development of TKI resistance. Deciphering the abnormally regulated DNA damage repair and proteins involved brings new insights into the therapy of leukemias. As a G2/M phase checkpoint kinase and a DNA damage repair checkpoint kinase engaged in the DNA damage response (DDR), along with an oncogenic driver present in various cancers, the particular involvement of Wee1 in DNA damage is far from clear. Deciphering its function and targeting it via modulating DNA repair pathways is important for improving our understanding of cancer treatment. Methods Wee1 expression was assessed in cell lines using RT-qPCR and western blot, and Wee1 knockdown efficacy was validated using RT-qPCR, western blot, and immunofluorescence. Wee1 function was investigated by CCK-8, colony formation, and flow cytometry assay in vitro. Wee1 role in DNA repair and its interactions with other proteins were then studied using western blot, immunofluorescence, and double plasmid-repair studies. Finally, the CCK-8 and flow cytometry assay was utilized to investigate Wee1 and imatinib’s synergistic effect, and a CML mouse model was constructed to study Wee1’s role in carcinogenesis in vivo. Results Wee1 was reported to respond quickly to DDR in an ATM-γH2AX-MDC1-dependent way upon DNA double-strand breaks (DSBs) occurrence, and it regulated homologous recombination by stimulating the recruitment of critical proteins RAD51/BRCA1 upon DSB sites. Wee1 was also revealed to be abnormally upregulated in CML cells. Further suppression of Wee1 not only causes cell cycle arrest and inhibits the proliferation of cancer cells but also enhances CML cell sensitivity to Imatinib in vitro and in vivo, possibly through an excessive accumulation of overall DSBs. Conclusion Wee1 is extensively involved in the DRR signaling and DSB repair pathway. Inhibiting abnormally elevated Wee1 benefits CML therapy in both IM-resistant and IM-sensitive cells. Our data demonstrated that Wee1 participated in promoting cell proliferation and imatinib resistance in chronic myeloid leukemia via regulating DNA damage repair dependent on ATM-γH2AX-MDC1. In the fight against CML, Wee1’s dysregulation in the DNA damage repair mechanism of CML pathogenesis makes it a viable therapeutic target in clinical applications.

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