ArticleMolecular cancer therapeutics2012
MK-2206, a novel allosteric inhibitor of Akt, synergizes with gefitinib against malignant glioma via modulating both autophagy and apoptosis.
Article in Molecular cancer therapeutics, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 81 papers.
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Who cites it
81 citing papers in PubMed, 136 citations in OpenAlex.
- Preclinical and early clinical evaluation of the oral AKT inhibitor, MK-2206, for the treatment of acute myelogenous leukemia.Clinical cancer research : an official journal of the American Association for Cancer Research · 2014Trial
- Disrupting Akt-Wnt/β-catenin signaling suppresses glioblastoma stem cell growth and tumor progression in immunocompetent mice.Journal of neuro-oncology · 2026Article
- Article
- The role of autophagy in cancer: from molecular mechanism to therapeutic window.Frontiers in immunology · 2025Review
- Protein phosphatase-1 regulates the binding of filamin C to FILIP1 in cultured skeletal muscle cells under mechanical stress.Scientific reports · 2024Article
- Anti-Cancer Strategy Based on Changes in the Role of Autophagy Depending on the Survival Environment and Tumorigenesis Stages.Molecules (Basel, Switzerland) · 2024Review
- Is Autophagy Targeting a Valid Adjuvant Strategy in Conjunction with Tyrosine Kinase Inhibitors?Cancers · 2024Review
- Delivery of US28 by incoming HCMV particles rapidly attenuates Akt activity to suppress HCMV lytic replication in monocytes.Science signaling · 2024Article
- Autophagy-enhancing ATG16L1 polymorphism is associated with improved clinical outcome and T-cell immunity in chronic HIV-1 infection.Nature communications · 2024Article
- Article
- Targeting EGFR/PI3K/AKT/mTOR Signaling in Hepatocellular Carcinoma.Pharmaceutics · 2023Review
- MK-2206 Alleviates Renal Fibrosis by Suppressing the Akt/mTOR Signaling Pathway In Vivo and In Vitro.Cells · 2022Article
- Single-Cell Transcriptomic Profiling of Human Retinal Organoids Revealed a Role of IGF1-PHLDA1 Axis in Photoreceptor Precursor Specification.Investigative ophthalmology & visual science · 2022Article
- Glypican 1 promotes proliferation and migration in esophagogastric adenocarcinoma via activating AKT/GSK/β-catenin pathway.Journal of gastrointestinal oncology · 2022Article
- Tumorous expression of NAC1 restrains antitumor immunity through the LDHA-mediated immune evasion.Journal for immunotherapy of cancer · 2022Article
- Studies on Biological and Molecular Effects of Small-Molecule Kinase Inhibitors on Human Glioblastoma Cells and Organotypic Brain Slices.Life (Basel, Switzerland) · 2022Article
- Development of actionable targets of multi-kinase inhibitors (AToMI) screening platform to dissect kinase targets of staurosporines in glioblastoma cells.Scientific reports · 2022Article
- Evaluating the Effects of Separate and Concomitant Use of MK-2206 and Salinomycin on Prostate Cancer Cell Line.Reports of biochemistry & molecular biology · 2022Article
- Golgi phosphoprotein 3 induces autophagy and epithelial-mesenchymal transition to promote metastasis in colon cancer.Cell death discovery · 2022Article
- Elongation factor-2 kinase is a critical determinant of the fate and antitumor immunity of CD8Science advances · 2022Article
21 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
12 authors at 3 institutions in 2 countries.
Funding
Abstract
Gefitinib, a small molecule inhibitor of the epidermal growth factor receptor tyrosine kinase, has been shown to induce autophagy as well as apoptosis in tumor cells. Yet, how to use autophagy and apoptosis to improve therapeutic efficacy of this drug against cancer remains to be explored. We reported here that MK-2206, a potent allosteric Akt inhibitor currently in phase I trials in patients with solid tumors, could reinforce the cytocidal effect of gefitinib against glioma. We found that cotreatment with gefitinib and MK-2206 increased the cytotoxicity of this growth factor receptor inhibitor in the glioma cells, and the CompuSyn synergism/antagonism analysis showed that MK-2206 acted synergistically with gefitinib. The benefit of the combinatorial treatment was also shown in an intracranial glioma mouse model. In the presence of MK-2206, there was a significant increase in apoptosis in glioma cells treated with gefitinib. MK-2206 also augmented the autophagy-inducing effect of gefitinib, as evidenced by increased levels of the autophagy marker, LC3-II. Inhibition of autophagy by silencing of the key autophagy gene, beclin 1 or 3-MA, further increased the cytotoxicity of this combinatorial treatment, suggesting that autophagy induced by these agents plays a cytoprotective role. Notably, at 48 hours following the combinatorial treatment, the level of LC3-II began to decrease but Bim was significantly elevated, suggesting a switch from autophagy to apoptosis. On the basis of the synergistic effect of MK-2206 on gefitinib observed in this study, the combination of these two drugs may be utilized as a new therapeutic regimen for malignant glioma.
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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.