ArticleClinical cancer research : an official journal of the American Association for Cancer Research2016
Parallel In Vivo Assessment of Drug Phenotypes at Various Time Points during Systemic BRAF Inhibition Reveals Tumor Adaptation and Altered Treatment Vulnerabilities.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 21 citations in OpenAlex.
- Development and Pre-clinical Feasibility of a Catheter-Based Platform for Interventional Phase-0 Drug Response Measurements.Annals of biomedical engineering · 2026Article
- An Interventional Radiology Method for In Situ Assessments of Cancer Drug Response: Preclinical Development, Feasibility, and Safety.Radiology. Imaging cancer · 2025Article
- Histone deacetylases in the regulation of cell death and survival mechanisms in resistant BRAF-mutant cancers.Cancer drug resistance (Alhambra, Calif.) · 2025Review
- In vivo vulnerabilities to GPX4 and HDAC inhibitors in drug-persistent versus drug-resistant BRAFCell reports. Medicine · 2024Article
- Machine-learning aided in situ drug sensitivity screening predicts treatment outcomes in ovarian PDX tumors.Translational oncology · 2022Article
- Strategic, feasibility, economic, and cultural aspects of phase 0 approaches: Is it time to change the drug development process in order to increase productivity?Clinical and translational science · 2022Review
- The Translational and Regulatory Development of an Implantable Microdevice for Multiple Drug Sensitivity Measurements in Cancer Patients.IEEE transactions on bio-medical engineering · 2022Article
- Self-Expanding Anchors for Stabilizing Percutaneously Implanted Microdevices in Biological Tissues.Micromachines · 2021Article
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- Phase 0/microdosing approaches: time for mainstream application in drug development?Nature reviews. Drug discovery · 2020Review
- An interventional image-guided microdevice implantation and retrieval method for in-vivo drug response assessment.Medical physics · 2019Article
- Functional precision cancer medicine-moving beyond pure genomics.Nature medicine · 2017Article
- Integrating functional genomics to accelerate mechanistic personalized medicine.Cold Spring Harbor molecular case studies · 2017Review
- CD147 silencing inhibits tumor growth by suppressing glucose transport in melanoma.Oncotarget · 2016Article
- Whole-transcriptomic Profile of SK-MEL-3 Melanoma Cells Treated with the Histone Deacetylase Inhibitor: Trichostatin A.Cancer genomics & proteomicsArticle
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
Abstract
purposeTreatment of BRAF-mutated melanoma tumors with BRAF inhibitor-based therapy produces high response rates, but of limited duration in the vast majority of patients. Published investigations of resistance mechanisms suggest numerous examples of tumor adaptation and signal transduction bypass mechanisms, but without insight into biomarkers that would predict which mechanism will predominate. Monitoring phenotypic response of multiple adaptive mechanisms simultaneously within the same tumor as it adapts during treatment has been elusive. EXPERIMENTAL
designThis study reports on a method to provide a more complete understanding of adaptive tumor responses. We simultaneously measured in vivo antitumor activity of 12 classes of inhibitors, which are suspected of enabling adaptive escape mechanisms, at various time points during systemic BRAF inhibition. We used implantable microdevices to release multiple compounds into distinct regions of a tumor to measure the efficacy of each compound independently and repeated these measurements as tumors progressed on systemic BRAF treatment.
resultsWe observed varying phenotypic responses to specific inhibitors before, during, and after prolonged systemic treatment with BRAF inhibitors. Our results specifically identify PI3K, PDGFR, EGFR, and HDAC inhibitors as becoming significantly more efficacious during systemic BRAF inhibition. The sensitivity to other targeted inhibitors remained mostly unchanged, whereas local incremental sensitivity to PLX4720 declined sharply.
conclusionsThese findings suggest redundancy of several resistance mechanisms and may help identify optimal constituents of more effective combination therapy in BRAF-mutant melanoma. They also represent a new paradigm for dynamic measurement of adaptive signaling mechanisms within the same tumor during therapy. Clin Cancer Res; 22(24); 6031-8. ©2016 AACR.
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