LIN9 and NEK2 Are Core Regulators of Mitotic Fidelity That Can Be Therapeutically Targeted to Overcome Taxane Resistance

Roberts, Melyssa S.; Sahni, Jennifer M.; Schrock, Morgan S.; Piemonte, Katrina M.; Weber-Bonk, Kristen L.; Seachrist, Darcie D.; Avril, Stefanie; Anstine, Lindsey J.; Singh, Salendra; Sizemore, Steven T.; Varadan, Vinay; Summers, Matthew K.; Keri, Ruth A.

doi:10.1158/0008-5472.can-19-3466

Cited by 27 publications

(26 citation statements)

References 49 publications

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“…Seven of the 13 genes were highly expressed in testis, but low in other tissues. None of the signature genes except TERT was cataloged by the expert-curated Cancer Gene Census 44 (as of July 2020), although LIN9 and HELLS were recently implicated in cancer 45,46 . Mutations in HELLS, a gene encoding a lymphoidspecific helicase, cause the centromeric instability and facial anomalies (ICF) syndrome, a genetic disorder associated with short telomeres 47 .…”

Section: Resultsmentioning

confidence: 99%

Integrated analysis of telomerase enzymatic activity unravels an association with cancer stemness and proliferation

Noureen

et al. 2021

Nat Commun

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Active telomerase is essential for stem cells and most cancers to maintain telomeres. The enzymatic activity of telomerase is related but not equivalent to the expression of TERT, the catalytic subunit of the complex. Here we show that telomerase enzymatic activity can be robustly estimated from the expression of a 13-gene signature. We demonstrate the validity of the expression-based approach, named EXTEND, using cell lines, cancer samples, and non-neoplastic samples. When applied to over 9,000 tumors and single cells, we find a strong correlation between telomerase activity and cancer stemness. This correlation is largely driven by a small population of proliferating cancer cells that exhibits both high telomerase activity and cancer stemness. This study establishes a computational framework for quantifying telomerase enzymatic activity and provides new insights into the relationships among telomerase, cancer proliferation, and stemness.

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Section: Resultsmentioning

confidence: 99%

Integrated analysis of telomerase enzymatic activity unravels an association with cancer stemness and proliferation

Noureen

et al. 2021

Nat Commun

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“…DNA topoisomerase 2-alpha ( TOP2A ), exodeoxyribonuclease 1 ( EXO1 ), serine/threonine-protein kinase Nek2 ( NEK2 ), baculoviral IAP repeat-containing protein 5 ( BIRC5 ), hyaluronan mediated motility receptor ( HMMR ), structural maintenance of chromosomes protein 4 ( SMC4 ), bloom syndrome protein ( BLM ), casein kinase I isoform epsilon ( CSNK1E ), cytoskeleton-associated protein 5 ( CKAP5 ), and inner centromere protein ( INCENP ) were identified as the hub genes based on the degrees of nodes which were more than 10 ( Figure 2 a) [ 11 ]. TOP2A , EXO1 , NEK2 , BIRC5 , SMC4 , BLM , CSNK1E , CKAP5 , and INCENP were related to DNA replication and cell division, and HMMR was related to cell motility [ 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 ]. The detailed functions of the hub genes are described in the discussion section and Supplementary Table S3 .…”

Section: Resultsmentioning

confidence: 99%

“…Furthermore, current reports have showed NEK2, as an important cyclin, has the functions of regulating the assembly and separation of centrosomes, the formation of spindles, and the precise separation of chromosomes [ 16 , 17 ]. In addition, NEK2 may also become an important marker for tumor differentiation and prognosis detection, and is an important potential target for cancer treatment [ 18 ].…”

Section: Discussionmentioning

confidence: 99%

Analysis of m6A RNA Methylation-Related Genes in Liver Hepatocellular Carcinoma and Their Correlation with Survival

Zhu

et al. 2021

IJMS

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N6-methyladenosine (m6A) modification on RNA plays an important role in tumorigenesis and metastasis, which could change gene expression and even function at multiple levels such as RNA splicing, stability, translocation, and translation. In this study, we aim to conduct a comprehensive analysis on m6A RNA methylation-related genes, including m6A RNA methylation regulators and m6A RNA methylation-modified genes, in liver hepatocellular carcinoma, and their relationship with survival and clinical features. Data, which consist of the expression of widely reported m6A RNA methylation-related genes in liver hepatocellular carcinoma from The Cancer Genome Atlas (TCGA), were analyzed by one-way ANOVA, Univariate Cox regression, a protein–protein interaction network, gene enrichment analysis, feature screening, a risk prognostic model, correlation analysis, and consensus clustering analysis. In total, 405 of the m6A RNA methylation-related genes were found based on one-way ANOVA. Among them, DNA topoisomerase 2-alpha (TOP2A), exodeoxyribonuclease 1 (EXO1), ser-ine/threonine-protein kinase Nek2 (NEK2), baculoviral IAP repeat-containing protein 5 (BIRC5), hyaluronan mediated motility receptor (HMMR), structural maintenance of chromosomes protein 4 (SMC4), bloom syndrome protein (BLM), ca-sein kinase I isoform epsilon (CSNK1E), cytoskeleton-associated protein 5 (CKAP5), and inner centromere protein (INCENP), which were m6A RNA methylation-modified genes, were recognized as the hub genes based on the protein–protein interaction analysis. The risk prognostic model showed that gender, AJCC stage, grade, T, and N were significantly different between the subgroup with the high and low risk groups. The AUC, the evaluation parameter of the prediction model which was built by RandomForest, was 0.7. Furthermore, two subgroups were divided by consensus clustering analysis, in which stage, grade, and T differed. We identified the important genes expressed significantly among two clusters, including uridine-cytidine kinase 2 (UCK2), filensin (BFSP1), tubulin-specific chaperone D (TBCD), histone-lysine N-methyltransferase PRDM16 (PRDM16), phosphorylase b ki-nase regulatory subunit alpha (PHKA2), serine/threonine-protein kinase BRSK2 (BRSK2), Arf-GAP with coiled-coil (ACAP3), general transcription factor 3C polypep-tide 2 (GTF3C2), and guanine nucleotide exchange factor MSS4 (RABIF). In our study, the m6A RNA methylation-related genes in liver hepatocellular carcinoma were analyzed systematically, including the expression, interaction, function, and prognostic values, which provided an important theoretical basis for m6A RNA methylation in liver cancer. The nine important m6A-related genes could be prognostic markers in the survival time of patients.

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“…Regulation of MT functions at the mitotic spindle are critical for functionality of the taxanes, and disruptions of these functions provide avenues for taxane resistance. NIMA-related Kinase 2 (NEK2) is a regulator of centrosome separation, which is a prerequisite for mitotic spindle assembly [ 87 , 88 ]. Both NEK2 and LIN9, the transcriptional regulator of NEK2, are elevated with taxane resistance in TNBC cells [ 87 , 89 ].…”

Section: Taxane Resistance In Breast Cancermentioning

confidence: 99%

“…NIMA-related Kinase 2 (NEK2) is a regulator of centrosome separation, which is a prerequisite for mitotic spindle assembly [ 87 , 88 ]. Both NEK2 and LIN9, the transcriptional regulator of NEK2, are elevated with taxane resistance in TNBC cells [ 87 , 89 ]. Inhibition of either NEK2 or LIN9 expression restored drug sensitivity by inducing mitotic errors and apoptosis.…”

Section: Taxane Resistance In Breast Cancermentioning

confidence: 99%

Mechanisms of Taxane Resistance

Maloney

Hoover

Morejon-Lasso

et al. 2020

Cancers

129

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The taxane family of chemotherapy drugs has been used to treat a variety of mostly epithelial-derived tumors and remain the first-line treatment for some cancers. Despite the improved survival time and reduction of tumor size observed in some patients, many have no response to the drugs or develop resistance over time. Taxane resistance is multi-faceted and involves multiple pathways in proliferation, apoptosis, metabolism, and the transport of foreign substances. In this review, we dive deeper into hypothesized resistance mechanisms from research during the last decade, with a focus on the cancer types that use taxanes as first-line treatment but frequently develop resistance to them. Furthermore, we will discuss current clinical inhibitors and those yet to be approved that target key pathways or proteins and aim to reverse resistance in combination with taxanes or individually. Lastly, we will highlight taxane response biomarkers, specific genes with monitored expression and correlated with response to taxanes, mentioning those currently being used and those that should be adopted. The future directions of taxanes involve more personalized approaches to treatment by tailoring drug–inhibitor combinations or alternatives depending on levels of resistance biomarkers. We hope that this review will identify gaps in knowledge surrounding taxane resistance that future research or clinical trials can overcome.

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LIN9 and NEK2 Are Core Regulators of Mitotic Fidelity That Can Be Therapeutically Targeted to Overcome Taxane Resistance

Abstract: Resistance to chemotherapy is a major hurdle for treating cancer patients. Combining NEK2 inhibitors with taxanes may be viable approach for improving patient outcomes by enhancing mitotic defects induced by taxanes alone.

Cited by 27 publications

References 49 publications

Integrated analysis of telomerase enzymatic activity unravels an association with cancer stemness and proliferation

Integrated analysis of telomerase enzymatic activity unravels an association with cancer stemness and proliferation

Analysis of m6A RNA Methylation-Related Genes in Liver Hepatocellular Carcinoma and Their Correlation with Survival

Mechanisms of Taxane Resistance

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