ArticleBritish journal of cancer2024
Dynamic genomic changes in methotrexate-resistant human cancer cell lines beyond DHFR amplification suggest potential new targets for preventing drug resistance.
Article in British journal of cancer, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 9 citations in OpenAlex.
- A complex mutational signature generated by cytarabine resistance.NAR cancer · 2026Article
- Single-cell multimodal profiling of pan-cancer cell lines uncovers gene regulatory principles underlying intrinsic cell states and environmental features.Nature communications · 2026Article
- Single-cell multimodal profiling of pan-cancer cell lines uncovers gene regulatory principles underlying intrinsic cell states and environmental features.bioRxiv : the preprint server for biology · 2026Article
- Dysfunctional DNA Mismatch Repair Drives the Evolution of Gene Amplification in MTX-Resistant Human Colorectal Cancer Cells.International journal of molecular sciences · 2026Article
- Individualized treatment and key prognostic biomarkers based on folate metabolism in patients with pancreatic cancer.Translational cancer research · 2026Article
- The Art of Domesticating Proteins: How Cancer Cells Adapt to Therapeutic and Environmental Stressors.International journal of molecular sciences · 2026Review
- Extrachromosomal DNA and cancer: function, formation, and clinical implications.Journal of experimental & clinical cancer research : CR · 2026Review
- Investigation of 6-thioguanine as a strategy to overcome methotrexate resistance in a mouse model of leptomeningeal carcinomatosis.Journal of neuro-oncology · 2025Article
- EccDNA-Driven VPS41 Amplification Alleviates Genotoxic Stress via Lysosomal KAI1 Degradation.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- The role of extrachromosomal DNA in tumorigenesis and progression.Frontiers in oncology · 2025Review
- HDAC-driven mechanisms in anticancer resistance: epigenetics and beyond.Cancer drug resistance (Alhambra, Calif.) · 2024Review
- Astaxanthin Co-treatment with Low Dose Methotrexate Increases the Cell Cycle Arrest and Ameliorates the Methotrexate-induced Inflammatory Response in NALM-6.International journal of molecular and cellular medicine · 2024Article
Corrections and comments
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Authors and funding
19 authors at 2 institutions in 1 country.
Funding
Abstract
backgroundAlthough DHFR gene amplification has long been known as a major mechanism for methotrexate (MTX) resistance in cancer, the early changes and detailed development of the resistance are not yet fully understood.
methodsWe performed genomic, transcriptional and proteomic analyses of human colon cancer cells with sequentially increasing levels of MTX-resistance.
resultsThe genomic amplification evolved in three phases (pre-amplification, homogenously staining region (HSR) and extrachromosomal DNA (ecDNA)). We confirm that genomic amplification and increased expression of DHFR, with formation of HSRs and especially ecDNAs, is the major driver of resistance. However, DHFR did not play a detectable role in the early phase. In the late phase (ecDNA), increase in FAM151B protein level may also have an important role by decreasing sensitivity to MTX. In addition, although MSH3 and ZFYVE16 may be subject to different posttranscriptional regulations and therefore protein expressions are decreased in ecDNA stages compared to HSR stages, they still play important roles in MTX resistance.
conclusionThe study provides a detailed evolutionary trajectory of MTX-resistance and identifies new targets, especially ecDNAs, which could help to prevent drug resistance. It also presents a proof-of-principal approach which could be applied to other cancer drug resistance studies.
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