ArticleCancer discovery2014
A novel AKT1 mutant amplifies an adaptive melanoma response to BRAF inhibition.
Article in Cancer discovery, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 113 papers, 1 of them a synthesis that pooled it.
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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
113 citing papers in PubMed, 1 synthesis or guideline pooled it, 177 citations in OpenAlex.
- Acquired BRAF inhibitor resistance: A multicenter meta-analysis of the spectrum and frequencies, clinical behaviour, and phenotypic associations of resistance mechanisms.European journal of cancer (Oxford, England : 1990) · 2015Pooled it
- Combined BRAF (Dabrafenib) and MEK inhibition (Trametinib) in patients with BRAFV600-mutant melanoma experiencing progression with single-agent BRAF inhibitor.Journal of clinical oncology : official journal of the American Society of Clinical Oncology · 2014Trial
- Genetic Drivers of Sensitivity or Resistance to RAS(ON) Multiselective Inhibitors in NRAS-Mutated Melanoma.Cancer research · 2026Article
- mTOR inhibition enhances the antitumor efficacy of pan-RAF-MEK blockade by inhibiting the ATF4-MTHFD2 pathway.Cell death & disease · 2026Article
- The structural heterogeneity of AKT autoinhibition.Protein science : a publication of the Protein Society · 2026Article
- Article
- Transcriptome-wide decoding the roles of aberrant splicing in melanoma MAPK-targeted resistance evolution.EMBO reports · 2025Article
- Sensitivity to immune checkpoint inhibitors in BRAF/MEK inhibitor refractory melanoma.Journal for immunotherapy of cancer · 2025Article
- Mechanistic insights into Rho/MRTF inhibition-induced apoptotic events and prevention of drug resistance in melanoma: implications for the involvement of pirin.Frontiers in pharmacology · 2025Article
- Targeting the PI3K/AKT/mTOR pathway in lung cancer: mechanisms and therapeutic targeting.Frontiers in pharmacology · 2025Review
- Navigating Therapeutic Challenges in BRAF-Mutated NSCLC: Non-V600 Mutations, Immunotherapy, and Overcoming Resistance.International journal of molecular sciences · 2024Review
- Characterization of two melanoma cell lines resistant to BRAF/MEK inhibitors (vemurafenib and cobimetinib).Cell communication and signaling : CCS · 2024Article
- Review
- Therapeutic advances of targeting receptor tyrosine kinases in cancer.Signal transduction and targeted therapy · 2024Review
- A phase 1 study of triple-targeted therapy with BRAF, MEK, and AKT inhibitors for patients with BRAF-mutated cancers.Cancer · 2024Article
- RAF and MEK Inhibitors in Non-Small Cell Lung Cancer.International journal of molecular sciences · 2024Review
- Evodiamine inhibits growth of vemurafenib drug-resistant melanoma via suppressing IRS4/PI3K/AKT signaling pathway.Journal of natural medicines · 2024Article
- Network-based prediction approach for cancer-specific driver missense mutations using a graph neural network.BMC bioinformatics · 2023Article
- Tumor Cell Resistance to the Inhibition of BRAF and MEK1/2.International journal of molecular sciences · 2023Review
- Somatic mutation spectrum of a Chinese cohort of pediatrics with vascular malformations.Orphanet journal of rare diseases · 2023Article
53 more citing papers are in PubMed but not listed here.
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Authors and funding
15 authors at 3 institutions in 1 country.
Funding
Abstract
BRAF inhibitor (BRAFi) therapy leads to remarkable anti melanoma responses, but the initial tumor shrinkage is commonly incomplete, providing a nidus for subsequent disease progression. Adaptive signaling may underlie early BRAFi resistance and influence the selection pattern for genetic variants, causing late, acquired resistance. We show here that BRAFi (or BRAFi + MEKi) therapy in patients frequently led to rebound phosphorylated AKT (p-AKT) levels in their melanomas early on-treatment. In cell lines, BRAFi treatment led to rebound levels of receptor tyrosine kinases (RTK; including PDGFRβ), phosphatidyl (3,4,5)-triphosphate (PIP3), pleckstrin homology domain recruitment, and p-AKT. PTEN expression limited this BRAFi-elicited PI3K-AKT signaling, which could be rescued by the introduction of a mutant AKT1 (Q79K) known to confer acquired BRAFi resistance. Functionally, AKT1(Q79K) conferred BRAFi resistance via amplification of BRAFi-elicited PI3K-AKT signaling. In addition, mitogen-activated protein kinase pathway inhibition enhanced clonogenic growth dependency on PI3K or AKT. Thus, adaptive or genetic upregulation of AKT critically participates in melanoma survival during BRAFi therapy.
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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.