CDK7 is a reliable prognostic factor and novel therapeutic target in epithelial ovarian cancer

Kim, Jihye; Cho, Young-Jae; Ryu, Ji-Yoon; Hwang, Ilseon; Han, Hee Dong; Ahn, Hyung Jun; Kim, Woo Young; Cho, Hanbyoul; Chung, Joon‐Yong; Hewitt, Stephen M.; Kim, Jae Hoon; Kim, Byoung-Gie; Bae, Duk-Soo; Choi, Chel Hun; Lee, Jeong‐Won

doi:10.1016/j.ygyno.2019.11.004

Cited by 23 publications

(23 citation statements)

References 34 publications

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“…Previous studies showed that high CDK7 expression correlates with worse clinical outcome in multiple cancer types [53][54][55][56]. Our data showed that CDK7 is highly expressed in NSCLC tumor tissue, and high CDK7 expression is a poor prognostic predictor.…”

Section: Discussionsupporting

confidence: 64%

CDK7 inhibitor THZ1 enhances antiPD-1 therapy efficacy via the p38α/MYC/PD-L1 signaling in non-small cell lung cancer

et al. 2020

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Background: The cyclin-dependent kinase 7 (CDK7) subunit of TFIIH regulates RNA polymerase-II-based transcription and promotes tumor progression. However, the mechanisms involved in CDK7-mediated immune evasion are unclear in non-small cell lung cancer (NSCLC). Methods: RNA silencing and pharmacologic inhibitors were used to evaluate the functions of CDK7/p38α/MYC/PD-L1 axis in cancer cell proliferation and antiPD-1 therapy resistance. Flow cytometry was performed to detect the status of the immune microenvironment after CDK7 inhibition and antiPD-1 therapy in vivo. CD8 depletion antibodies were used to assess the role of CD8 + T cells in combined CDK7 and PD-1 blockade. The associations among CDK7, p38α, MYC, PD-L1, infiltrating T cells, and survival outcomes were validated in two tissue microarrays and public transcriptomic data of NSCLC. Results: High CDK7 mRNA and protein levels were identified to be associated with poor prognosis in NSCLC. CDK7 silencing and CDK7 inhibitor THZ1 elicited apoptosis and suppressed tumor growth. Moreover, CDK7 ablation specifically suppressed p38α/MYC-associated genes, and THZ1 inhibited MYC transcriptional activity through downregulating p38α. CDK7 inhibition sensitized NSCLC to p38α inhibitor. Further, THZ1 suppressed PD-L1 expression by inhibiting MYC activity. THZ1 boosted antitumor immunity by recruiting infiltrating CD8 + T cells and synergized with antiPD-1 therapy. The CDK7/MYC/PD-L1 signature and infiltrating T cell status collectively stratified NSCLC patients into different risk groups. Conclusion: These data suggest that the combined CDK7 inhibitor THZ1 and antiPD-1 therapy can be an effective treatment in NSCLC.

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Section: Discussionsupporting

confidence: 64%

CDK7 inhibitor THZ1 enhances antiPD-1 therapy efficacy via the p38α/MYC/PD-L1 signaling in non-small cell lung cancer

et al. 2020

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“…Besides, CDK7 is also one component of TFIIH that phosphorylates RNAP II or other transcription factors, such as androgen receptor and ER (8). Thus far, accumulating studies have demonstrated that CDK7 is frequently overexpressed in diverse tumor tissues including gastric cancer, oral squamous cell carcinoma, and breast cancer (9)(10)(11)(12). Preclinical studies have confirmed that covalent CDK7 inhibitors selectively induce apoptosis in certain cancers, but not in normal human cells (13)(14)(15)(16)(17)(18).…”

Section: Introductionmentioning

confidence: 99%

Targeting Mutated p53 Dependency in Triple-Negative Breast Cancer Cells Through CDK7 Inhibition

Peng

Yang

et al. 2021

Front. Oncol.

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BackgroundCyclin-dependent kinase 7 (CDK7) is crucial for cell cycle progression and gene expression transcriptional regulation, which are often not assessed in cancer developing process. CDK7 inhibitors have emerged as promising drugs for treating diverse cancers, including breast cancer. However, the mechanism behind its anticancer effect has not been well investigated. Here, the possible mechanism of CDK7 inhibitors for treating human triple-negative breast cancer (TNBC) has been studied.MethodsThe effects of CDK7 inhibitors on breast cancer cells have been identified by measuring cell viability (Cell Counting Kit-8) and cell proliferation and calculating colony formation. The short hairpin RNA and short interfering RNA were used for the construction of knockdown cells. To assess the expression of associated proteins, western blot was used.ResultsThis study confirmed that, compared to hormone receptor-positive breast cancer cells, TNBC cells were more sensitive to THZ1, a novel CDK7 inhibitor. THZ1 treatment specifically downregulated mutated p53 in a dose- and time-dependent manner in TNBC cells with p53 mutation. Another CDK7 inhibitor, LDC4297, also potently interfered with the expression of mutated p53. Furthermore, endogenous CDK7 expression was positively correlated with the levels of mutated p53 in TNBC cells with p53 mutation. Downregulating mutated p53 expression significantly suppressed the proliferation of TNBC cells with p53 mutation.ConclusionOur findings demonstrated that targeting CDK7 was an effective approach for the treatment of TNBC with p53 mutation.

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“…CDK7 was signi cantly associated with the invasive phenotype of OC and had an independent prognostic ability for OC recurrence. Moreover, CDK7 may be a potential therapeutic target for OC patients regardless of platinum sensitivity or drug resistance [24]. Qi et al, found that CYPA is involved in the progression and metastasis of OC, providing a promising therapeutic target for OC therapy [25].…”

Section: Discussionmentioning

confidence: 99%

Knockdown of ZNF280A inhibits the development and progression of ovarian cancer

Zhu

et al. 2020

Preprint

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Background: Ovarian cancer (OC) is one of the leading causes of death from gynecological malignancies worldwide. Abnormal expression of zinc finger proteins has been extensively reported to be involved in malignant progression in a variety of cancers. However, clinical significance and biological roles of ZNF280A in the field of OC are poorly known. Methods: In this study, we demonstrated that ZNF280A was highly expressed in OC tissues compared with adjacent normal tissues. Further, ZNF280A was significantly associated with clinical staging, infiltration, lymphatic metastasis, metastasis, and tumor recurrence of OC patients. Additionally, data of in vitro experiments indicated that knockdown of ZNF280A by its shRNA dramatically reduces the proliferation and migration ability of OC cells, while enhancing the cell apoptosis. Results: It was also verified by animal experiments that ZNF280A silencing would affect the growth of OC in vivo. Our study investigated the involvement of ZNF280A in the prognosis, progression and metastasis of OC. Conclusions: Therefore, our study identified ZNF280A as an optional prognostic factor in OC patients and can be used as a potential therapeutic target for the treatment of OC.

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CDK7 is a reliable prognostic factor and novel therapeutic target in epithelial ovarian cancer

Cited by 23 publications

References 34 publications

CDK7 inhibitor THZ1 enhances antiPD-1 therapy efficacy via the p38α/MYC/PD-L1 signaling in non-small cell lung cancer

CDK7 inhibitor THZ1 enhances antiPD-1 therapy efficacy via the p38α/MYC/PD-L1 signaling in non-small cell lung cancer

Targeting Mutated p53 Dependency in Triple-Negative Breast Cancer Cells Through CDK7 Inhibition

Knockdown of ZNF280A inhibits the development and progression of ovarian cancer

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