ArticleLeukemia2022
In vivo PDX CRISPR/Cas9 screens reveal mutual therapeutic targets to overcome heterogeneous acquired chemo-resistance.
Article in Leukemia, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
What it found
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Who cites it
16 citing papers in PubMed, 15 citations in OpenAlex.
- BUB signaling in cancer and molecular insights into targeted therapies.Communications biology · 2026Review
- A platform of serially transplantable AML PDX models covering subgroups for which no cell lines exist.HemaSphere · 2026Article
- Comparison of Cell Line-Derived and Patient-Derived Xenograft Technologies in Oncology (Review).Bulletin of experimental biology and medicine · 2026Article
- CRISPR-based functional genomics for dissecting therapeutic dependency in primary acute myeloid leukemia samples.Molecular cell · 2026Article
- Functional Genomics: Principles and Methods.Advances in experimental medicine and biology · 2026Review
- Review
- Acquired resistance in cancer: towards targeted therapeutic strategies.Nature reviews. Cancer · 2025Review
- Inhibition of platin-induced BCL2 increase overcomes chemoresistance in squamous cell carcinoma of the head and neck through resensitization to cell death.Translational oncology · 2025Article
- Review
- Advances in the application of patient-derived xenograft models in acute leukemia resistance.Cancer drug resistance (Alhambra, Calif.) · 2025Review
- Nodularin-R Synergistically Enhances Abiraterone Against Castrate- Resistant Prostate Cancer via PPP1CA Inhibition.Journal of cellular and molecular medicine · 2024Article
- Advancements in CRISPR screens for the development of cancer immunotherapy strategies.Molecular therapy oncolytics · 2023Review
- Increased MCL1 dependency leads to new applications of BH3-mimetics in drug-resistant neuroblastoma.British journal of cancer · 2023Article
- Chromatin accessibility landscape of relapsed pediatric B-lineage acute lymphoblastic leukemia.Nature communications · 2023Article
- Radiation Sensitivity: The Rise of Predictive Patient-Derived Cancer Models.Seminars in radiation oncology · 2023Review
- Patient-derived xenograft models in cancer therapy: technologies and applications.Signal transduction and targeted therapy · 2023Review
Corrections and comments
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Authors and funding
21 authors at 6 institutions in 2 countries.
Funding
Abstract
Resistance towards cancer treatment represents a major clinical obstacle, preventing cure of cancer patients. To gain mechanistic insights, we developed a model for acquired resistance to chemotherapy by treating mice carrying patient derived xenografts (PDX) of acute lymphoblastic leukemia with widely-used cytotoxic drugs for 18 consecutive weeks. In two distinct PDX samples, tumors initially responded to treatment, until stable disease and eventually tumor re-growth evolved under therapy, at highly similar kinetics between replicate mice. Notably, replicate tumors developed different mutations in TP53 and individual sets of chromosomal alterations, suggesting independent parallel clonal evolution rather than selection, driven by a combination of stochastic and deterministic processes. Transcriptome and proteome showed shared dysregulations between replicate tumors providing putative targets to overcome resistance. In vivo CRISPR/Cas9 dropout screens in PDX revealed broad dependency on BCL2, BRIP1 and COPS2. Accordingly, venetoclax re-sensitized derivative tumors towards chemotherapy, despite genomic heterogeneity, demonstrating direct translatability of the approach. Hence, despite the presence of multiple resistance-associated genomic alterations, effective rescue treatment for polychemotherapy-resistant tumors can be identified using functional testing in preclinical models.
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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.