ArticleProceedings of the National Academy of Sciences of the United States of America2018
Disruption of the anaphase-promoting complex confers resistance to TTK inhibitors in triple-negative breast cancer.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 61 papers.
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Who cites it
61 citing papers in PubMed, 106 citations in OpenAlex.
- Chromosomal instability in cancer: sources, consequences and new therapeutic opportunities.Signal transduction and targeted therapy · 2026Review
- Chromosomal instability promotes cell migration and invasion via EFEMP1 secretion into extracellular vesicles.The EMBO journal · 2026Article
- Genome-Wide CRISPR Screens Identify ABCG2-Mediated Drug Resistance to the Threonine Tyrosine Kinase (TTK) Inhibitor CFI-402257 in Breast Cancer.International journal of molecular sciences · 2026Article
- FOXM1 Signaling Network Transcriptionally Upregulates Expression of Proteins Involved in Mitotic Progression to Induce High Proliferation and Chromosomal Instability in Androgen Receptor-Low Triple-Negative Breast Cancer.International journal of molecular sciences · 2026Article
- Artemis (DCLRE1C) Acts as a Target to Enhance Radiotherapy Response in Triple-Negative Breast Cancer.Cancers · 2025Article
- TTK promotes mitophagy by regulating ULK1 phosphorylation and pre-mRNA splicing to inhibit mitochondrial apoptosis in bladder cancer.Cell death and differentiation · 2025Article
- Targeting monopolar spindle kinase I (Mps1 or TTK) induces radiosensitization in syngeneic models of triple negative breast cancer (TNBC) and potentiates type I interferon (T1IFN) signaling.Neoplasia (New York, N.Y.) · 2025Article
- CRISPR screening approaches in breast cancer research.Cancer metastasis reviews · 2025Review
- Anapc5 and Anapc7 as genetic modifiers of KIF18A function in fertility and mitotic progression.Scientific reports · 2025Article
- Threonine and tyrosine kinase (TTK) mRNA and protein expression in breast cancer; prognostic significance in the neoadjuvant setting.Histopathology · 2025Article
- Targeting TTK Inhibits Tumorigenesis of T-Cell Lymphoma Through Dephosphorylating p38α and Activating AMPK/mTOR Pathway.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Gene Co-Expression Network Analysis Associated with Endometrial Cancer Tumorigenesis and Survival Outcomes.International journal of molecular sciences · 2024Article
- Targeting the EGFR and Spindle Assembly Checkpoint Pathways in Oral Cancer: A Plausible Alliance to Enhance Cell Death.Cancers · 2024Article
- Functional RNAi Screening Identifies G2/M and Kinetochore Components as Modulators of TNFα/NF-κB Prosurvival Signaling in Head and Neck Squamous Cell Carcinoma.Cancer research communications · 2024Article
- Identification of KIFC1 as a putative vulnerability in lung cancers with centrosome amplification.Cancer gene therapy · 2024Article
- Mitotic kinases are emerging therapeutic targets against metastatic breast cancer.Cell division · 2024Review
- Transcriptomic analysis revealed potential regulatory biomarkers and repurposable drugs for breast cancer treatment.Cancer reports (Hoboken, N.J.) · 2024Article
- Article
- The two sides of chromosomal instability: drivers and brakes in cancer.Signal transduction and targeted therapy · 2024Review
- TRMT13 inhibits the growth of papillary thyroid cancer by targeting ANAPC4.Acta biochimica et biophysica Sinica · 2024Article
1 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
12 authors at 2 institutions in 1 country.
Funding
Abstract
TTK protein kinase (TTK), also known as Monopolar spindle 1 (MPS1), is a key regulator of the spindle assembly checkpoint (SAC), which functions to maintain genomic integrity. TTK has emerged as a promising therapeutic target in human cancers, including triple-negative breast cancer (TNBC). Several TTK inhibitors (TTKis) are being evaluated in clinical trials, and an understanding of the mechanisms mediating TTKi sensitivity and resistance could inform the successful development of this class of agents. We evaluated the cellular effects of the potent clinical TTKi CFI-402257 in TNBC models. CFI-402257 induced apoptosis and potentiated aneuploidy in TNBC lines by accelerating progression through mitosis and inducing mitotic segregation errors. We used genome-wide CRISPR/Cas9 screens in multiple TNBC cell lines to identify mechanisms of resistance to CFI-402257. Our functional genomic screens identified members of the anaphase-promoting complex/cyclosome (APC/C) complex, which promotes mitotic progression following inactivation of the SAC. Several screen candidates were validated to confer resistance to CFI-402257 and other TTKis using CRISPR/Cas9 and siRNA methods. These findings extend the observation that impairment of the APC/C enables cells to tolerate genomic instability caused by SAC inactivation, and support the notion that a measure of APC/C function could predict the response to TTK inhibition. Indeed, an APC/C gene expression signature is significantly associated with CFI-402257 response in breast and lung adenocarcinoma cell line panels. This expression signature, along with somatic alterations in genes involved in mitotic progression, represent potential biomarkers that could be evaluated in ongoing clinical trials of CFI-402257 or other TTKis.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.