ArticleThe Journal of clinical endocrinology and metabolism2012
The Akt inhibitor MK2206 synergizes, but perifosine antagonizes, the BRAF(V600E) inhibitor PLX4032 and the MEK1/2 inhibitor AZD6244 in the inhibition of thyroid cancer cells.
Article in The Journal of clinical endocrinology and metabolism, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers, 1 of them a synthesis that pooled it.
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Who cites it
33 citing papers in PubMed, 1 synthesis or guideline pooled it, 56 citations in OpenAlex.
- Design of new drugs for medullary thyroid carcinoma.Frontiers in oncology · 2022Pooled it
- PKM2-Mediated Glycolytic Reprogramming in Thyroid Cancer: Mechanistic Insights and Therapeutic Potential.Molecules (Basel, Switzerland) · 2026Review
- Targeted therapy for head and neck cancer: signaling pathways and clinical studies.Signal transduction and targeted therapy · 2023Review
- State of the Art in the Current Management and Future Directions of Targeted Therapy for Differentiated Thyroid Cancer.International journal of molecular sciences · 2022Review
- Nuclear interaction of Arp2/3 complex and BRAFAmerican journal of cancer research · 2022Article
- Central and peripheral emetic loci contribute to vomiting evoked by the Akt inhibitor MK-2206 in the least shrew model of emesis.European journal of pharmacology · 2021Article
- Combinatorial Therapies in Thyroid Cancer: An Overview of Preclinical and Clinical Progresses.Cells · 2020Review
- The MEK1/2 Inhibitor AZD6244 Sensitizes BRAF-Mutant Thyroid Cancer to Vemurafenib.Medical science monitor : international medical journal of experimental and clinical research · 2018Article
- In-vitro and in-vivo combined effect of ARQ 092, an AKT inhibitor, with ARQ 087, a FGFR inhibitor.Anti-cancer drugs · 2017Article
- Dual Inhibition of PI3K/AKT and MEK/ERK Pathways Induces Synergistic Antitumor Effects in Diffuse Intrinsic Pontine Glioma Cells.Translational oncology · 2017Article
- Dual EGFR and BRAF blockade overcomes resistance to vemurafenib in BRAF mutated thyroid carcinoma cells.Cancer cell international · 2017Article
- MK2206 overcomes the resistance of human liver cancer stem cells to sorafenib by inhibition of pAkt and upregulation of pERK.Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine · 2016Article
- Mathematical Modeling of Therapy-induced Cancer Drug Resistance: Connecting Cancer Mechanisms to Population Survival Rates.Scientific reports · 2016Article
- PI3K/AKT Pathway and Its Mediators in Thyroid Carcinomas.Molecular diagnosis & therapy · 2016Review
- New therapies for dedifferentiated papillary thyroid cancer.International journal of molecular sciences · 2015Review
- Recent Advances on Small-Molecule Survivin InhibitorsCurrent medicinal chemistry · 2015Article
- Selective use of vandetanib in the treatment of thyroid cancer.Drug design, development and therapy · 2015Review
- PDK1-mTOR signaling pathway inhibitors reduce cell proliferation in MK2206 resistant neuroblastoma cells.Cancer cell international · 2015Article
- Update: the status of clinical trials with kinase inhibitors in thyroid cancer.The Journal of clinical endocrinology and metabolism · 2014Review
- Genetics and epigenetics of sporadic thyroid cancer.Molecular and cellular endocrinology · 2014Review
Corrections and comments
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Authors and funding
3 authors at 2 institutions in 1 country.
Funding
Abstract
purposeThe purpose of the study was to explore optimal combinations of currently actively developed drugs for dually targeting the Ras → Raf → MAPK kinase (MEK) → MAPK/ERK (MAPK) and the phosphatidylinositol 3-kinase/Akt pathways as effective treatments for thyroid cancer. EXPERIMENTAL
designWe tested the combinations of the Akt inhibitors MK2206 or perifosine with the BRAF(V600E) inhibitor PLX4032 or the MEK1/2 inhibitor AZD6244 in thyroid cancer cells harboring both the BRAF(V600E) and PIK3CA mutations.
resultsWe found that MK2206 could potently, when used alone, and synergistically, when combined with either PLX4032 or AZD6244, inhibit thyroid cancer cell growth with all the combination index values lower than 1. Perifosine could potently inhibit thyroid cancer cell growth when used alone, but a strong antagonism occurred between this drug and PLX4032 or AZD6244 in the inhibition of thyroid cancer cell growth with all combination index values higher than 1. Combinations of MK2206 with PLX4032 or AZD6244 dramatically enhanced G1 cell cycle arrest induced by each drug alone. However, G2 cell cycle arrest uniquely induced by perifosine alone and G1 cell cycle arrest induced by PLX4032 or AZD6244 were both reversed by combination treatments, providing a mechanism for their antagonism. All these drugs could correspondingly inhibit the MAPK and phosphatidylinositol 3-kinase/Akt signalings, confirming their expected target effects.
conclusionsWe demonstrated, unexpectedly, opposite outcomes of MK2206 and perifosine in their combinational treatments with BRAF(V600E)/MEK inhibitors in thyroid cancer cells. The data may help appropriate selection of these prominent drugs for clinical trials of combination therapies for thyroid cancer.
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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.