Modeling critical dosing strategies for stromal-induced resistance to cancer therapy

• Published in: NPJ systems biology and applications Vol. 11; no. 1; pp. 16 - 17
• Main Authors: Kraut, Anna K., Garvey, Colleen M., Strelez, Carly, Mumenthaler, Shannon M., Foo, Jasmine
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 06.02.2025; Nature Publishing Group; Nature Portfolio
• Subjects: 631/114; 631/67; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - pharmacology; Bioinformatics; Biology; Biomedical and Life Sciences; Cancer; Cancer therapies; Cell Line, Tumor; Cetuximab - administration & dosage; Cetuximab - pharmacology; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - pathology; Combination therapy; Computational Biology/Bioinformatics; Computer Appl. in Life Sciences; Dosage; Dose-Response Relationship, Drug; Drug dosages; Drug resistance; Drug Resistance, Neoplasm - drug effects; Environmental factors; Epidermal growth factor; Epidermal growth factor receptors; ErbB Receptors - antagonists & inhibitors; ErbB Receptors - metabolism; Fibroblasts; Humans; Life Sciences; Lung cancer; Mathematical models; Melanoma; Models, Biological; Monoclonal antibodies; Neoplasms - drug therapy; Neoplasms - pathology; Optimization; Ordinary differential equations; Secretome; Stromal cells; Stromal Cells - drug effects; Stromal Cells - metabolism; Stromal Cells - pathology; Systems Biology; Tumor cells; Tumor Microenvironment - drug effects; Tumors
• DOI: 10.1038/s41540-025-00495-0
• ISSN: 2056-7189

Complex interactions between stromal cells, tumor cells and therapies can influence environmental factors that in turn impact anticancer treatment efficacy. Disentangling these phenomena is critical for understanding treatment response and designing effective dosing strategies. We propose a mathematical model for a common tumor-stromal interaction motif where stromal cells secrete factors that promote drug resistance. We demonstrate that the presence of this interaction modulates the therapeutic dose window of efficacy and can lead to nonmonotonic treatment response. We consider combination strategies that target stromal cells and their secretome, and identify strategies that constrain drug concentrations within the efficacious window for long-term response. We explore an experimental dataset from colorectal cancer cells treated with anti-EGFR targeting therapy, cetuximab, where cancer-associated fibroblasts increase epidermal growth factor secretion under treatment. We apply our general approach to identify a critical drug concentration threshold and study effective dosing regimens for single-drug and combination therapies.