ArticleProceedings of the National Academy of Sciences of the United States of America2015
BRAF inhibitor resistance mediated by the AKT pathway in an oncogenic BRAF mouse melanoma model.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 90 papers.
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90 citing papers in PubMed, 143 citations in OpenAlex.
- scGSDR: Harnessing gene semantics for single-cell pharmacological profiling.Communications biology · 2025Article
- Inhibition of BRD4 attenuated IFNγ-induced apoptosis in colorectal cancer organoids.BMC cancer · 2025Article
- Second-generation BRAF inhibitor Encorafenib resistance is regulated by NCOA4-mediated iron trafficking in the drug-resistant malignant melanoma cells.Scientific reports · 2025Article
- CD9 shapes glucocorticoid sensitivity in pediatric B-cell precursor acute lymphoblastic leukemia.Haematologica · 2024Article
- Review
- scRank infers drug-responsive cell types from untreated scRNA-seq data using a target-perturbed gene regulatory network.Cell reports. Medicine · 2024Article
- AMBRA1 levels predict resistance to MAPK inhibitors in melanoma.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- LPCAT1 promotes melanoma cell proliferation via Akt signaling.Oncology reports · 2024Article
- Resistance to BRAF inhibition explored through single circulating tumour cell molecular profiling in BRAF-mutant non-small-cell lung cancer.British journal of cancer · 2024Article
- HSPA8 Activates Wnt/β-Catenin Signaling to Facilitate BRAF V600E Colorectal Cancer Progression by CMA-Mediated CAV1 Degradation.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- Tumor Cell Resistance to the Inhibition of BRAF and MEK1/2.International journal of molecular sciences · 2023Review
- PAK1 and Therapy Resistance in Melanoma.Cells · 2023Review
- Epigenetic suppression of PGC1α (PPARGC1A) causes collateral sensitivity to HMGCR-inhibitors within BRAF-treatment resistant melanomas.Nature communications · 2023Article
- Advances in transposable elements: from mechanisms to applications in mammalian genomics.Frontiers in genetics · 2023Review
- A unique hyperdynamic dimer interface permits small molecule perturbation of the melanoma oncoprotein MITF for melanoma therapy.Cell research · 2023Article
- SRC-RAC1 signaling drives drug resistance to BRAF inhibition in de-differentiated cutaneous melanomas.NPJ precision oncology · 2022Article
- Proteasomal down-regulation of the proapoptotic MST2 pathway contributes to BRAF inhibitor resistance in melanoma.Life science alliance · 2022Article
- Long-term non-invasive drug treatments in adult zebrafish that lead to melanoma drug resistance.Disease models & mechanisms · 2022Article
- The pleiotropic roles of circular and long noncoding RNAs in cutaneous melanoma.Molecular oncology · 2022Review
- Article
30 more citing papers are in PubMed but not listed here.
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12 authors at 7 institutions in 2 countries.
Funding
Abstract
BRAF (v-raf murine sarcoma viral oncogene homolog B) inhibitors elicit a transient anti-tumor response in ∼ 80% of BRAF(V600)-mutant melanoma patients that almost uniformly precedes the emergence of resistance. Here we used a mouse model of melanoma in which melanocyte-specific expression of Braf(V618E) (analogous to the human BRAF(V600E) mutation) led to the development of skin hyperpigmentation and nevi, as well as melanoma formation with incomplete penetrance. Sleeping Beauty insertional mutagenesis in this model led to accelerated and fully penetrant melanomagenesis and synchronous tumor formation. Treatment of Braf(V618E) transposon mice with the BRAF inhibitor PLX4720 resulted in tumor regression followed by relapse. Analysis of transposon insertions identified eight genes including Braf, Mitf, and ERas (ES-cell expressed Ras) as candidate resistance genes. Expression of ERAS in human melanoma cell lines conferred resistance to PLX4720 and induced hyperphosphorylation of AKT (v-akt murine thymoma viral oncogene homolog 1), a phenotype reverted by combinatorial treatment with PLX4720 and the AKT inhibitor MK2206. We show that ERAS expression elicits a prosurvival signal associated with phosphorylation/inactivation of BAD, and that the resistance of hepatocyte growth factor-treated human melanoma cells to PLX4720 can be reverted by treatment with the BAD-like BH3 mimetic ABT-737. Thus, we define a role for the AKT/BAD pathway in resistance to BRAF inhibition and illustrate an in vivo approach for finding drug resistance genes.
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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.