ArticlePLoS computational biology2015
Spatial heterogeneity in drug concentrations can facilitate the emergence of resistance to cancer therapy.
Article in PLoS computational biology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 78 papers.
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Who cites it
78 citing papers in PubMed, 135 citations in OpenAlex.
- The value of target-site physiologically-based pharmacokinetics for high-affinity small molecules: a mechanistic foundation for precision dosing in oncology and hematology.Cancer chemotherapy and pharmacology · 2026Article
- Narrowing of glioma vascular caliber via chronic VEGFR2 blockade improves the uniformity of focused ultrasound-mediated small molecule drug delivery.Journal of controlled release : official journal of the Controlled Release Society · 2026Article
- Biomaterial-based strategies for postoperative residual tumors: From margin clearance to immune control and tissue repair.Materials today. Bio · 2026Review
- Organoids to Model Tumor Microenvironment in Progression of Pathogenesis and Treatment Resistance in Glioblastoma Multiforme.Brain sciences · 2026Review
- Hierarchies of resistance to DNA damage response inhibitors: from pathway restoration to replication stress tolerance.Experimental hematology & oncology · 2026Review
- The effect of the fitness gradient on fixation probability.Nature communications · 2026Article
- Cytotoxic and Cytostatic Effects of Nanoformulated Fenretinide on MG63 Osteosarcoma Cells.Pharmaceutics · 2026Article
- Linking spatial drug heterogeneity to microbial growth dynamics in theory and experiment.PLoS computational biology · 2026Article
- Multidimensional tumor heterogeneity and its role in therapeutic resistance.Frontiers in immunology · 2026Review
- Deciphering and steering population-level response under spatial drug heterogeneity on microhabitat structures.bioRxiv : the preprint server for biology · 2025Article
- Developments in nanotechnology approaches for the treatment of solid tumors.Experimental hematology & oncology · 2025Review
- Review
- Evolutionary rescue model informs strategies for driving cancer cell populations to extinction.bioRxiv : the preprint server for biology · 2025Article
- Neoadjuvant chemoimmunotherapy for esophageal squamous cell carcinoma with non-regional cervical lymph node metastasis: a retrospective pilot study.Frontiers in immunology · 2025Article
- Establishment and characterization of NCC-SS6-C1: a novel patient-derived cell line of synovial sarcoma.Human cell · 2024Article
- Competition for resources can reshape the evolutionary properties of spatial structure.PLoS computational biology · 2024Article
- Modeling spatial evolution of multi-drug resistance under drug environmental gradients.PLoS computational biology · 2024Article
- Mathematical modeling of the evolution of resistance and aggressiveness of high-grade serous ovarian cancer from patient CA-125 time series.PLoS computational biology · 2024Article
- The Impact of Inadequate Exposure to Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors on the Development of Resistance in Non-Small-Cell Lung Cancer Cells.International journal of molecular sciences · 2024Article
- Competition for resources can reshape the evolutionary properties of spatial structure.bioRxiv : the preprint server for biology · 2024Article
18 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
3 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Acquired resistance is one of the major barriers to successful cancer therapy. The development of resistance is commonly attributed to genetic heterogeneity. However, heterogeneity of drug penetration of the tumor microenvironment both on the microscopic level within solid tumors as well as on the macroscopic level across metastases may also contribute to acquired drug resistance. Here we use mathematical models to investigate the effect of drug heterogeneity on the probability of escape from treatment and the time to resistance. Specifically we address scenarios with sufficiently potent therapies that suppress growth of all preexisting genetic variants in the compartment with the highest possible drug concentration. To study the joint effect of drug heterogeneity, growth rate, and evolution of resistance, we analyze a multi-type stochastic branching process describing growth of cancer cells in multiple compartments with different drug concentrations and limited migration between compartments. We show that resistance is likely to arise first in the sanctuary compartment with poor drug penetrations and from there populate non-sanctuary compartments with high drug concentrations. Moreover, we show that only below a threshold rate of cell migration does spatial heterogeneity accelerate resistance evolution, otherwise deterring drug resistance with excessively high migration rates. Our results provide new insights into understanding why cancers tend to quickly become resistant, and that cell migration and the presence of sanctuary sites with little drug exposure are essential to this end.
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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.