ArticleCell reports2021
A systematic analysis of signaling reactivation and drug resistance.
Article in Cell reports, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
What it found
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
29 citing papers in PubMed.
- Inferring feedback regulation from static snapshots of a single signal.Biochemistry and biophysics reports · 2026Article
- A structure-based modeling approach identifies effective drug combinations for RAS-mutant acute myeloid leukemia.iScience · 2026Article
- Cancer drug response and resistance: molecular mechanisms and combating strategies.Signal transduction and targeted therapy · 2026Review
- IFN𝛾 and IFN𝛾 mimetics prevent IFN-I-mediated TB susceptibility by regulating iron metabolism and lipid peroxidation.bioRxiv : the preprint server for biology · 2026Article
- Network hypermotifs in biological systems: structure, dynamics, and functional implications.NPJ systems biology and applications · 2026Review
- Dual RAF inhibition outperforms RAF-MEK combinations for suppressing ERK signaling in KRAS mutant cells.NPJ systems biology and applications · 2026Article
- Zero-shot prediction of drug responses using biologically informed neural networks trained on phosphoproteomic timeseries.PLoS computational biology · 2026Article
- Phase II Trial of Vemurafenib and Sorafenib Combination in AdvancedJournal of immunotherapy and precision oncology · 2026Article
- Discovering anticancer drug target combinations via network-informed signaling-based approach.Communications medicine · 2025Article
- Systems Biology of the Cancer Cell.Annual review of biomedical engineering · 2025Review
- Molecular principles underlying aggressive cancers.Signal transduction and targeted therapy · 2025Review
- Towards an interpretable deep learning model of cancer.NPJ precision oncology · 2025Review
- cSTAR analysis identifies endothelial cell cycle as a key regulator of flow-dependent artery remodeling.Science advances · 2025Article
- Ras, RhoA, and vascular pharmacology in neurodevelopment and aging.Neurochemistry international · 2024Review
- Anticancer Target Combinations: Network-Informed Signaling-Based Approach to Discovery.bioRxiv : the preprint server for biology · 2024Article
- Cell-specific models reveal conformation-specific RAF inhibitor combinations that synergistically inhibit ERK signaling in pancreatic cancer cells.Cell reports · 2024Article
- The value of protein allostery in rational anticancer drug design: an update.Expert opinion on drug discovery · 2024Review
- Research into overcoming drug resistance in lung cancer treatment using CRISPR-Cas9 technology: a narrative review.Translational lung cancer research · 2024Review
- Cell State Transition Models Stratify Breast Cancer Cell Phenotypes and Reveal New Therapeutic Targets.Cancers · 2024Article
- Network-driven cancer cell avatars for combination discovery and biomarker identification for DNA damage response inhibitors.NPJ systems biology and applications · 2024Article
Corrections and comments
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Authors and funding
4 authors.
Funding
Abstract
Increasing evidence suggests that the reactivation of initially inhibited signaling pathways causes drug resistance. Here, we analyze how network topologies affect signaling responses to drug treatment. Network-dependent drug resistance is commonly attributed to negative and positive feedback loops. However, feedback loops by themselves cannot completely reactivate steady-state signaling. Newly synthesized negative feedback regulators can induce a transient overshoot but cannot fully restore output signaling. Complete signaling reactivation can only occur when at least two routes, an activating and inhibitory, connect an inhibited upstream protein to a downstream output. Irrespective of the network topology, drug-induced overexpression or increase in target dimerization can restore or even paradoxically increase downstream pathway activity. Kinase dimerization cooperates with inhibitor-mediated alleviation of negative feedback. Our findings inform drug development by considering network context and optimizing the design drug combinations. As an example, we predict and experimentally confirm specific combinations of RAF inhibitors that block mutant NRAS signaling.
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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.