ArticleClinical cancer research : an official journal of the American Association for Cancer Research2016
Personalized Preclinical Trials in BRAF Inhibitor-Resistant Patient-Derived Xenograft Models Identify Second-Line Combination Therapies.
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 77 papers.
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Who cites it
77 citing papers in PubMed, 134 citations in OpenAlex.
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- Combinatorial ERK Inhibition Enhances MAPK Pathway Suppression in BRAF-Mutant Melanoma.International journal of molecular sciences · 2025Article
- Combinatorial therapy regimens targeting preclinical models of melanoma resistant to immune checkpoint blockade.The Journal of clinical investigation · 2025Article
- The Roles of PTEN in Melanoma Suppression.Pigment cell & melanoma research · 2025Review
- PDX models for functional precision oncology and discovery science.Nature reviews. Cancer · 2025Review
- Improving Water Solubility and Skin Penetration of Ursolic Acid through a Nanofiber Process to Achieve Better In Vitro Anti-Breast Cancer Activity.Pharmaceutics · 2024Article
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- scNovel: a scalable deep learning-based network for novel rare cell discovery in single-cell transcriptomics.Briefings in bioinformatics · 2024Article
- Resveratrol as sensitizer in colorectal cancer plasticity.Cancer metastasis reviews · 2024Review
- Exploring the In Vitro and In Vivo Therapeutic Potential of BRAF and MEK Inhibitor Combination in NRAS-Mutated Melanoma.Cancers · 2023Article
17 more citing papers are in PubMed but not listed here.
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22 authors at 2 institutions in 1 country.
Funding
Abstract
purposeTo test second-line personalized medicine combination therapies, based on genomic and proteomic data, in patient-derived xenograft (PDX) models. EXPERIMENTAL
designWe established 12 PDXs from BRAF inhibitor-progressed melanoma patients. Following expansion, PDXs were analyzed using targeted sequencing and reverse-phase protein arrays. By using multi-arm preclinical trial designs, we identified efficacious precision medicine approaches.
resultsWe identified alterations previously described as drivers of resistance: NRAS mutations in 3 PDXs, MAP2K1 (MEK1) mutations in 2, BRAF amplification in 4, and aberrant PTEN in 7. At the protein level, re-activation of phospho-MAPK predominated, with parallel activation of PI3K in a subset. Second-line efficacy of the pan-PI3K inhibitor BKM120 with either BRAF (encorafenib)/MEK (binimetinib) inhibitor combination or the ERK inhibitor VX-11e was confirmed in vivo Amplification of MET was observed in 3 PDX models, a higher frequency than expected and a possible novel mechanism of resistance. Importantly, MET amplification alone did not predict sensitivity to the MET inhibitor capmatinib. In contrast, capmatinib as single agent resulted in significant but transient tumor regression in a PDX with resistance to BRAF/MEK combination therapy and high pMET. The triple combination capmatinib/encorafenib/binimetinib resulted in complete and sustained tumor regression in all animals.
conclusionsGenomic and proteomic data integration identifies dual-core pathway inhibition as well as MET as combinatorial targets. These studies provide evidence for biomarker development to appropriately select personalized therapies of patients and avoid treatment failures. See related commentary by Hartsough and Aplin, p. 1550.
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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.