A Novel CDK2/9 Inhibitor CYC065 Causes Anaphase Catastrophe and Represses Proliferation, Tumorigenesis, and Metastasis in Aneuploid Cancers

Kawakami, Masanori; Mustachio, Lisa Maria; Chen, Yulong; Chen, Zibo; Liu, Xiuxia; Wei, Cheng; Roszik, Jason; Kittai, Adam; Danilov, Alexey V.; Zhang, Xiaoshan; Fang, Bingliang; Wang, Jing; Heymach, John V.; Tyutyunyk‐Massey, Liliya; Freemantle, Sarah J.; Liu, Xi; Dmitrovsky, Ethan

doi:10.1158/1535-7163.mct-19-0987

Cited by 10 publications

(11 citation statements)

References 53 publications

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“…Similar observations have been made in non-malignant and mammary gland breast epithelial cells treated with CYC065 [ 17 ] and THZ1-treated fibroblasts [ 18 ]. In addition, we have shown that CYC065 and THZ1 inhibit the invasive capabilities of these cultures in line with other studies [ 24 , 48 ]. This is key as GBM invasion makes it extremely difficult to surgically resect, which causes high rates of tumour relapse [ 49 ].…”

Section: Discussionsupporting

confidence: 92%

Transcriptional CDK inhibitors, CYC065 and THZ1 promote Bim-dependent apoptosis in primary and recurrent GBM through cell cycle arrest and Mcl-1 downregulation

et al. 2021

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Activation of cyclin-dependent kinases (CDKs) contributes to the uncontrolled proliferation of tumour cells. Genomic alterations that lead to the constitutive activation or overexpression of CDKs can support tumourigenesis including glioblastoma (GBM), the most common and aggressive primary brain tumour in adults. The incurability of GBM highlights the need to discover novel and more effective treatment options. Since CDKs 2, 7 and 9 were found to be overexpressed in GBM, we tested the therapeutic efficacy of two CDK inhibitors (CKIs) (CYC065 and THZ1) in a heterogeneous panel of GBM patient-derived cell lines (PDCLs) cultured as gliomaspheres, as preclinically relevant models. CYC065 and THZ1 treatments suppressed invasion and induced viability loss in the majority of gliomaspheres, irrespective of the mutational background of the GBM cases, but spared primary cortical neurons. Viability loss arose from G2/M cell cycle arrest following treatment and subsequent induction of apoptotic cell death. Treatment efficacies and treatment durations required to induce cell death were associated with proliferation velocities, and apoptosis induction correlated with complete abolishment of Mcl-1 expression, a cell cycle-regulated antiapoptotic Bcl-2 family member. GBM models generally appeared highly dependent on Mcl-1 expression for cell survival, as demonstrated by pharmacological Mcl-1 inhibition or depletion of Mcl-1 expression. Further analyses identified CKI-induced Mcl-1 loss as a prerequisite to establish conditions at which the BH3-only protein Bim can efficiently induce apoptosis, with cellular Bim amounts strongly correlating with treatment efficacy. CKIs reduced proliferation and promoted apoptosis also in chick embryo xenograft models of primary and recurrent GBM. Collectively, these studies highlight the potential of these novel CKIs to suppress growth and induce cell death of patient-derived GBM cultures in vitro and in vivo, warranting further clinical investigation.

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Section: Discussionsupporting

confidence: 92%

Transcriptional CDK inhibitors, CYC065 and THZ1 promote Bim-dependent apoptosis in primary and recurrent GBM through cell cycle arrest and Mcl-1 downregulation

et al. 2021

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“…Recently, CDK family molecules have been used as novel molecular markers for tumor-targeted therapy. As a star molecule, CDK2 ( Kawakami et al, 2020 ) participates in classic pathways in various cancers, such as colorectal cancer ( Somarelli et al, 2020 ), neuroblastoma ( Poon et al, 2020 ), breast cancer ( Hur et al, 2020 ), hepatocellular carcinoma ( Hou et al, 2019 ), and prostate cancer ( Washino et al, 2019 ). However, there are few studies on the mechanism of CDK2 in lung cancer.…”

Section: Discussionmentioning

confidence: 99%

Identification of CDK2-Related Immune Forecast Model and ceRNA in Lung Adenocarcinoma, a Pan-Cancer Analysis

Liu

Chen

et al. 2021

Front. Cell Dev. Biol.

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BackgroundTumor microenvironment (TME) plays important roles in different cancers. Our study aimed to identify molecules with significant prognostic values and construct a relevant Nomogram, immune model, competing endogenous RNA (ceRNA) in lung adenocarcinoma (LUAD).Methods“GEO2R,” “limma” R packages were used to identify all differentially expressed mRNAs from Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. Genes with P-value <0.01, LogFC>2 or <-2 were included for further analyses. The function analysis of 250 overlapping mRNAs was shown by DAVID and Metascape software. By UALCAN, Oncomine and R packages, we explored the expression levels, survival analyses of CDK2 in 33 cancers. “Survival,” “survminer,” “rms” R packages were used to construct a Nomogram model of age, gender, stage, T, M, N. Univariate and multivariate Cox regression were used to establish prognosis-related immune forecast model in LUAD. CeRNA network was constructed by various online databases. The Genomics of Drug Sensitivity in Cancer (GDSC) database was used to explore correlations between CDK2 expression and IC50 of anti-tumor drugs.ResultsA total of 250 differentially expressed genes (DEGs) were identified to participate in many cancer-related pathways, such as activation of immune response, cell adhesion, migration, P13K-AKT signaling pathway. The target molecule CDK2 had prognostic value for the survival of patients in LUAD (P = 5.8e-15). Through Oncomine, TIMER, UALCAN, PrognoScan databases, the expression level of CDK2 in LUAD was higher than normal tissues. Pan-cancer analysis revealed that the expression, stage and survival of CDK2 in 33 cancers, which were statistically significant. Through TISIDB database, we selected 13 immunodepressants, 21 immunostimulants associated with CDK2 and explored 48 genes related to these 34 immunomodulators in cBioProtal database (P < 0.05). Gene Set Enrichment Analysis (GSEA) and Metascape indicated that 49 mRNAs were involved in PUJANA ATM PCC NETWORK (ES = 0.557, P = 0, FDR = 0), SIGNAL TRANSDUCTION (ES = –0.459, P = 0, FDR = 0), immune system process, cell proliferation. Forest map and Nomogram model showed the prognosis of patients with LUAD (Log-Rank = 1.399e-08, Concordance Index = 0.7). Cox regression showed that four mRNAs (SIT1, SNAI3, ASB2, and CDK2) were used to construct the forecast model to predict the prognosis of patients (P < 0.05). LUAD patients were divided into two different risk groups (low and high) had a statistical significance (P = 6.223e-04). By “survival ROC” R package, the total risk score of this prognostic model was AUC = 0.729 (SIT1 = 0.484, SNAI3 = 0.485, ASB2 = 0.267, CDK2 = 0.579). CytoHubba selected ceRNA mechanism medicated by potential biomarkers, 6 lncRNAs-7miRNAs-CDK2. The expression of CDK2 was associated with IC50 of 89 antitumor drugs, and we showed the top 20 drugs with P < 0.05.ConclusionIn conclusion, our study identified CDK2 related immune forecast model, Nomogram model, forest map, ceRNA network, IC50 of anti-tumor drugs, to predict the prognosis and guide targeted therapy for LUAD patients.

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“… 44–49 Enhanced anaphase catastrophe prevented preexisting supernumerary centrosomes from clustering and eradicated aneuploid cancer cells while relatively sparing immortalized bronchial epithelial cells. 44–49 The pan-CDK or selective CDK2 inhibitors seliciclib, 44 dinaciclib, 50 CCT68127 49 and CYC065 (Fadraciclib) 48 each caused anaphase catastrophe. Notably, CCT68127 49 and CYC065 48 that each inhibit CDK2 activity also conferred statistically-significant repression of tumor growth in mice bearing syngeneic or patient-derived xenografts (PDXs) of lung cancers.…”

Section: Introductionmentioning

confidence: 99%

“… 44–49 The pan-CDK or selective CDK2 inhibitors seliciclib, 44 dinaciclib, 50 CCT68127 49 and CYC065 (Fadraciclib) 48 each caused anaphase catastrophe. Notably, CCT68127 49 and CYC065 48 that each inhibit CDK2 activity also conferred statistically-significant repression of tumor growth in mice bearing syngeneic or patient-derived xenografts (PDXs) of lung cancers. CYC065-treatment of these mice led to lung cancers having multipolar or abnormal mitosis.…”

Section: Introductionmentioning

confidence: 99%

CDK2 inhibition disorders centrosome stoichiometry and alters cellular outcomes in aneuploid cancer cells

Chen,

Liu,

Kawakami

et al. 2023

Cancer Biology & Therapy

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Cyclin-dependent Kinase 2 (CDK2) inhibition prevents supernumerary centrosome clustering. This causes multipolarity, anaphase catastrophe and apoptotic death of aneuploid cancers. This study elucidated how CDK2 antagonism affected centrosome stoichiometry. Focused ion beam scanning electron microscopy (FIB-SEM) and immunofluorescent imaging were used. Studies interrogated multipolar mitosis after pharmacologic or genetic repression of CDK2. CDK2/9 antagonism with CYC065 (Fadraciclib)-treatment disordered centrosome stoichiometry in aneuploid cancer cells, preventing centrosome clustering. This caused ring-like chromosomes or multipolar cancer cells to form before onset of cell death. Intriguingly, CDK2 inhibition caused a statistically significant increase in single centrioles rather than intact centrosomes with two centrioles in cancer cells having chromosome rings or multipolarity. Statistically significant alterations in centrosome stoichiometry were undetected in other mitotic cancer cells. To confirm this pharmacodynamic effect, CDK2 but not CDK9 siRNA-mediated knockdown augmented cancer cells with chromosome ring or multipolarity formation. Notably, engineered gain of CDK2, but not CDK9 expression, reversed emergence of cancer cells with chromosome rings or multipolarity, despite CYC065-treatment. In marked contrast, CDK2 inhibition of primary human alveolar epithelial cells did not confer statistically significant increases of cells with ring-like chromosomes or multipolarity. Hence, CDK2 antagonism caused differential effects in malignant versus normal alveolar epithelial cells. Translational relevance was confirmed by CYC065-treatment of syngeneic lung cancers in mice. Mitotic figures in tumors exhibited chromosome rings or multipolarity. Thus, CDK2 inhibition preferentially disorders centrosome stoichiometry in cancer cells. Engaging this disruption is a strategy to explore against aneuploid cancers in future clinical trials.

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A Novel CDK2/9 Inhibitor CYC065 Causes Anaphase Catastrophe and Represses Proliferation, Tumorigenesis, and Metastasis in Aneuploid Cancers

Cited by 10 publications

References 53 publications

Transcriptional CDK inhibitors, CYC065 and THZ1 promote Bim-dependent apoptosis in primary and recurrent GBM through cell cycle arrest and Mcl-1 downregulation

Transcriptional CDK inhibitors, CYC065 and THZ1 promote Bim-dependent apoptosis in primary and recurrent GBM through cell cycle arrest and Mcl-1 downregulation

Identification of CDK2-Related Immune Forecast Model and ceRNA in Lung Adenocarcinoma, a Pan-Cancer Analysis

CDK2 inhibition disorders centrosome stoichiometry and alters cellular outcomes in aneuploid cancer cells

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