ArticleProceedings of the National Academy of Sciences of the United States of America2022
Hyper-active RAS/MAPK introduces cancer-specific mitotic vulnerabilities.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 23 citations in OpenAlex.
- Modulation of Mitogen-Activated Protein Kinase (MAPK) Signaling Pathway in Gastrointestinal Cancers by Phytochemicals.Pharmaceutical research · 2026Review
- A Model for the Diversity Explosion Fundamental to Metastasis.bioRxiv : the preprint server for biology · 2025Article
- Cancer-associated USP28 missense mutations disrupt 53BP1 interaction and p53 stabilization.Nature communications · 2025Article
- Non-autonomous insulin signaling delays mitotic progression in C. elegans germline stem and progenitor cells.PLoS genetics · 2024Article
- BubR1 and SIRT2: Insights into aneuploidy, aging, and cancer.Seminars in cancer biology · 2024Review
- Human aneuploid cells depend on the RAF/MEK/ERK pathway for overcoming increased DNA damage.Nature communications · 2024Article
- Article
- The two sides of chromosomal instability: drivers and brakes in cancer.Signal transduction and targeted therapy · 2024Review
- An Aurora kinase A-BOD1L1-PP2A B56 Axis promotes chromosome segregation fidelity.bioRxiv : the preprint server for biology · 2024Article
- Natural products targeting the MAPK-signaling pathway in cancer: overview.Journal of cancer research and clinical oncology · 2024Review
- Hyperdiploid acute lymphoblastic leukemia in children withHemaSphere · 2024Article
Corrections and comments
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Authors and funding
9 authors at 2 institutions in 1 country.
Funding
Abstract
Aneuploidy, the incorrect number of whole chromosomes, is a common feature of tumors that contributes to their initiation and evolution. Preventing aneuploidy requires properly functioning kinetochores, which are large protein complexes assembled on centromeric DNA that link mitotic chromosomes to dynamic spindle microtubules and facilitate chromosome segregation. The kinetochore leverages at least two mechanisms to prevent aneuploidy: error correction and the spindle assembly checkpoint (SAC). BubR1, a factor involved in both processes, was identified as a cancer dependency and therapeutic target in multiple tumor types; however, it remains unclear what specific oncogenic pressures drive this enhanced dependency on BubR1 and whether it arises from BubR1's regulation of the SAC or error-correction pathways. Here, we use a genetically controlled transformation model and glioblastoma tumor isolates to show that constitutive signaling by RAS or MAPK is necessary for cancer-specific BubR1 vulnerability. The MAPK pathway enzymatically hyperstimulates a network of kinetochore kinases that compromises chromosome segregation, rendering cells more dependent on two BubR1 activities: counteracting excessive kinetochore-microtubule turnover for error correction and maintaining the SAC. This work expands our understanding of how chromosome segregation adapts to different cellular states and reveals an oncogenic trigger of a cancer-specific defect.
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Registered trials
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