Combination cancer therapies aim to improve the probability and magnitude of therapeutic responses and reduce the likelihood of acquired resistance in an individual patient. However, drugs are tested in clinical trials on genetically diverse patient populations. We show here that patient-to-patient variability and independent drug action are sufficient to explain the superiority of many FDA-approved drug combinations in the absence of drug synergy or additivity. This is also true for combinations tested in patient-derived tumor xenografts. In a combination exhibiting independent drug action, each patient benefits solely from the drug to which his or her tumor is most sensitive, with no added benefit from other drugs. Even when drug combinations exhibit additivity or synergy in pre-clinical models, patient-to-patient variability and low cross-resistance make independent action the dominant mechanism in clinical populations. This insight represents a different way to interpret trial data and a different way to design combination therapies.
CORR Insights®: Micrometastatic Drug Screening Platform Shows Heterogeneous Response to MAP Chemotherapy in Osteosarcoma Cell Lines
Should chemotherapy plus immune checkpoint inhibition be the standard front-line therapy for patients with metastatic non-small cell lung cancer?
Glucocorticoids and checkpoint tyrosine kinase inhibitors stimulate rat pancreatic beta cell proliferation differentially
Comparison of null models for combination drug therapy reveals Hand model as biochemically most plausible
Concise Review: Towards the Clinical Translation of Induced Pluripotent Stem Cell-Derived Blood Cells-Ready for Take-Off
Conformational ensemble of native α-synuclein in solution as determined by short-distance crosslinking constraint-guided discrete molecular dynamics simulations
The interaction of immune checkpoint inhibitor plus chemotherapy in non-small-cell lung cancer: subadditivity, additivity or synergism?
Co-delivery of dual chemo-drugs with precisely controlled, high drug loading polymeric micelles for synergistic anti-cancer therapy
Experimentally-driven mathematical modeling to improve combination targeted and cytotoxic therapy for HER2+ breast cancer
Phenotype-based probabilistic analysis of heterogeneous responses to cancer drugs and their combination efficacy
Biphasic Mathematical Model of Cell-Drug Interaction That Separates Target-Specific and Off-Target Inhibition and Suggests Potent Targeted Drug Combinations for Multi-Driver Colorectal Cancer Cells
Simvastatin increases temozolomide-induced cell death by targeting the fusion of autophagosomes and lysosomes.
CD44 Targeting Mediated by Polymeric Nanoparticles and Combination of Chlorine TPCS2a -PDT and Docetaxel-Chemotherapy for Efficient Killing of Breast Differentiated and Stem Cancer Cells In Vitro
Comparing the intra-tumoral distribution of Gemcitabine, 5-Fluorouracil, and Capecitabine in a murine model of pancreatic ductal adenocarcinoma
Measurement of ex vivo resistance to proteasome inhibitors, IMiDs, and daratumumab during multiple myeloma progression.
COMBSecretomics: A pragmatic methodological framework for higher-order drug combination analysis using secretomics
Commentary on ICH guideline on genomic sampling and data management-enabling opportunities in drug development and patient treatment.
Urothelial carcinoma: the development of FGFR inhibitors in combination with immune checkpoint inhibitors.
Network pharmacology modeling identifies synergistic Aurora B and ZAK interaction in triple-negative breast cancer.
Chitosan Hydrogels for Synergistic Delivery of Chemotherapeutics to Triple Negative Breast Cancer Cells and Spheroids.
Crizotinib induced antitumor activity and synergized with chemotherapy and hormonal drugs in breast cancer cells via downregulating MET and estrogen receptor levels.
Cutting down the time to identify challenging tumor therapeutic targets and drug combinations using synthetic lethal approaches
Phenotypic Plasticity, Bet-Hedging, and Androgen Independence in Prostate Cancer: Role of Non-Genetic Heterogeneity
High-Throughput Flow Cytometry Drug Combination Discovery with Novel Synergy Analysis Software, SynScreen
Effects of trastuzumab on locoregional recurrence in human epidermal growth factor receptor 2-overexpressing breast cancer patients treated with chemotherapy and radiotherapy
Decursin induces apoptosis in glioblastoma cells, but not in glial cells via a mitochondria-related caspase pathway
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