MK-2206

Our finding demonstrate that single knockdown of Dsg2 or Dsc2 could promote proliferation, motility and invasion in triple-negative MDA-MB-231 and luminal MCF-7 cells. Nevertheless, the underlying mechanisms were cellular context-specific and distinct.

The findings from this study demonstrate the anticancer activity of GPX8 in HCC by inactivating the Hsc70/AKT pathway. The results suggest a possible therapeutic target for HCC.

The AhR antagonist CH223191 and Akt inhibitor MK2206 suppressed indoxyl sulfate-induced proliferation of HCT-116 cells...Furthermore, indoxyl sulfate increased the sensitivity of CRC cells to EGF by upregulating EGFR expression. These findings suggest that indoxyl sulfate may be an important link between CKD and CRC aggravation.

P2, N=108, Active, not recruiting, National Cancer Institute (NCI)

These results suggest that emodin attenuates ARP in mice, and the underlying mechanism might involve inhibition of the AKT/ERK/NF-κB/VEGF pathways and the induction of apoptosis mediated by JNK and p38.

Our research offers valuable insights into the use of AF for treating NSCLC and PDAC. It highlights AF's cancer cell selectivity, establishes CA12 as a predictive biomarker for AF sensitivity, and underscores the enhanced efficacy of AF when combined with MK2206 and other therapeutics. These findings pave the way for further exploration of AF in cancer treatment, particularly in identifying patient populations most likely to benefit from its use and in optimizing combination therapies for improved patient outcomes.

In summary, DKK1 can promote the PI3K-AKT signaling pathway in tumor cells and then could induce neuritogenesis and facilitate PNI. MK2206 may be a potential therapeutic target drug for HNSCC patients with PNI.

Vascular endothelial growth factor A (VEGFA) enzyme-linked immunosorbent assay (ELISA) assay, Western blot analysis, and MK-2206 were used to investigate the specific mechanism mediated by FHL2...We further confirmed that FHL2 also promoted NSCLC tumor growth in vivo. Our study revealed the role of FHL2 in NSCLC and the mechanism by which FHL2 promotes NSCLC tumorigenesis, providing novel insights into targeted therapy for NSCLC.

P1, N=62, Active, not recruiting, National Cancer Institute (NCI)

However, these effects were attenuated when MK2206, a PI3K/AKT inhibitor, was applied. In conclusion, upregulation of Plk3 sensitized NSCLC cells toward DDP, which provides a potential target to restore DDP chemoresponse. We provided novel evidence that the PTEN/PI3K/AKT signaling pathway could be regulated by Plk3 through phosphorylation of PTEN and highlighted the critical role of Plk3 in the DDP resistance of NSCLC.

HL-60 cells were treated with Idelalisib, MK-2206, and Everolimus, which respectively are selective inhibitors of phosphatidylinositol-3-kinase (PI3K), AKT, and the mammalian target of rapamycin (mTOR), either individually or in combination. A combination of PI3K/AKT/mTOR pathway inhibitors regulates the expression of genes involved in glycolysis, pyruvate dehydrogenase complex (PDH), and the tricarboxylic acid (TCA) cycle and interferes with metabolic reprogramming and immune evasion mechanisms of AML leukemic cells. Combinational therapy approaches to block these pathways might be a promising and novel therapeutic strategy for targeting the metabolic requirements of AML cells.

PFKFB3 can enhance ATC cell proliferation and migration via the WNT/β-catenin signaling pathway and plays a crucial role in the regulation of aerobic glycolysis in ATC cells.

A deeper genomic and biological characterization of KRAS mutants might sustain the development of more efficient and long-lasting therapeutic options for patients harbouring KRAS-driven GC.

Endoxifen, a secondary tamoxifen metabolite, is a potent antiestrogen exhibiting estrogen receptor alpha (ERα) binding at nanomolar concentrations. ENDX's effects on AKT were phenocopied by siRNA-mediated PKCβ1 knockdown or treatment with the pan-AKT inhibitor, MK-2206, while overexpression of constitutively active AKT diminished ENDX-induced apoptosis. These findings, which identify PKCβ1 as an ENDX target, indicate that PKCβ1/ENDX interactions suppress AKT signaling and induce apoptosis in breast cancer.

In addition, protective autophagy was initiated by MK2206 stimulation, while blocking autophagy further increased ferroptosis and markedly enhanced the anti-tumor activity of MK2206. In a word, inhibiting AKT activated ferroptosis through FTO/YTHDF2/GPX4 axis to suppress colon cancer progression, which raised FTO/GPX4 as potential biomarkers and targets in colorectal cancer therapy.

Triple-negative breast cancer (TNBC) has an aggressive clinical course, and paclitaxel (PTX)-based chemotherapy remains the main therapeutic drug. In vivo, xenograft tumors of an MTDH knockdown+MK2206 group treated with PTX were the smallest compared to other groups. In short, MTDH inhibits TNBC chemosensitivity to PTX by activating the AKT/GSK-3β signaling pathway.

In addition, FOXO3a levels were elevated by the treatment of PTX-resistant cells with MK2206 (an Akt inhibitor) and U0126 (a MEK inhibitor). Collectively, our findings indicate that metformin exerts its effect on FOXO3a through the activation of AMPK and the inhibition of protein kinase B (Akt) and MAPK/extracellular signal-regulated kinase (MEK), culminating in the suppression of stemness in paclitaxel-resistant NSCLC cells.

Our findings not only uncovered the mechanism of metabolic reprogramming in EGFR-activated GBM but also provided a combinatorial therapeutic strategy for clinical GBM management.

In turn, RBM45 promoted the utility of lipid in HCCs through accelerating both de novo lipogenesis and fatty acid β oxidation, which required the participation of Rictor, a core component of mTORC2 that has been demonstrated to modulate lipid metabolism potently, as well as ACSL1/ACSL4, two key enzymes of long-chain fatty acid synthesis. When the first-line chemotherapy drug sorafenib is combined with a PI3K/AKT/mTOR pathway inhibitor (MK2206 is an AKT inhibitor, rapamycin is a mTOR inhibitor, and inhibiting RBM45 can significantly inhibit Rictor), cell cycle, proliferation, lipid metabolism reprogramming, and hepatocarcinogenesis can be significantly inhibited, while apoptosis can be significantly enhanced.

Furthermore, the AKT inhibitor MK2206 enhanced the inhibitory effect of Ezetimibe on the cell cycle and proliferation ability of TNBC cells overexpressing PDGFRβ. In xenograft tumor models, we also found that Ezetimibe inhibited TNBC growth, an effect that can be blocked by overexpression of PDGFR or activation of AKT. In summary, we have demonstrated that EZ inhibits the PDGFR/AKT pathway, thereby halting TNBC cycle progression and tumor growth.

MK-2206 failed to induce clinical responses in patients with incurable ACC. AKT inhibition may diminish MYB protein levels, although the effect was highly variable among patients. Novel approaches to target MYB in ACC are needed.

Notably, the overexpression of SCARNA12 activated PI3K/AKT pathway in SW620 cells, and the malignancy degree of CRC cells was attenuated after treatment with MK2206 (a specific AKT inhibitor). Our findings demonstrated that SCARNA12 plays an oncogenic role in CRC progression and can be used as a potential diagnostic biomarker for CRC.

Increased Akt signaling led to dysregulation of antigen presentation, and treatment with the Akt inhibitor MK2206-2HCl restored antigen presentation in Parkin-deficient tumors...Furthermore, low Parkin expression correlated with reduced patient response to immunotherapy. Overall, these results identify a role for Parkin deficiency in promoting tumor immune evasion that may explain the poor prognosis associated with loss of Parkin across multiple types of cancer.

APS restored GSIS in LPS-stimulated pancreatic β-cells by activating the Akt/mTOR/GLUT2 signaling pathway.

Treatment with MK-2206, an AKT pharmacological inhibitor, suppressed EGF-induced cell proliferation and transformed colony growth. In conclusion, this study demonstrated the potential of LicoD as a preventive agent for skin carcinogenesis.

EVL anti-apoptotic effects were inhibited by treatment with MK-2206, a selective AKT inhibitor. Furthermore, EVL suppressed DOX-induced cardiotoxicity through autophagy/mitophagy and AKT activation but did not attenuate DOX-induced apoptosis or reduction in viability in MCF-7 cells. Altogether, EVL can protect cardiomyocytes from DOX-induced apoptosis and toxicity without reducing DOX antitumor effects, allowing safer chemotherapy.

GLCM_SS+ also showed distinct gene profiles enriched in immune signaling. Further experiments are planned to verify the radiogenomics association with GLCM_SS+ sensitivity to MK-2206.

PLCD3 promotes malignant cell behaviors in esophageal squamous cell carcinoma via the PI3K/AKT/P21 signaling and could serve as a potential target for ESCC treatment.

Together, our findings reveal a novel mechanism of action associated with the anti-GBM effects of osimertinib involving ER stress-regulated paraptosis. Furthermore, we identify a TRIP13-driven resistance mechanism against Osimertinib in GBM and offer a combination strategy using MK-2206 to overcome such resistance.

Pre-incubation with LY294002, MK2206, AR-A014418, or U0126 was consistently found to significantly aggravate PD-induced inhibition of viability. The anti-leukemic activity of PD was further validated using primary samples from de novo AML patients. Given the results of the present study, PD may be a potent therapeutic candidate for the treatment of AML.

MCF7 MAGI1 KO cells exposed to ionizing radiations or cisplatin had reduced expression of DNA repair proteins and showed increased sensitivity towards PARP1 inhibition using olaparib. Treatment with PI3K and AKT inhibitors (alpelisib and MK-2206) restored the expression of DNA repair proteins and sensitized cells to fulvestrant...Pharmacological and genomic evidence indicate HDACs as regulators of MAGI1 expression. Our findings provide a new view on MAGI1 function in cancer and identify potential treatment options to improve the management of ER BC patients with low MAGI1 levels.

In addition, the AKT inhibitor MK2206 neutralized the pro-oncogenic effects of ZYX on the HCC cells, whereas the AKT activator SC79 restored the proliferation, migration and invasion of HCC cells with ZYX knockdown. Taken together, ZYX promotes the malignant progression of HCC by activating AKT/mTOR signaling pathway, and is a potential therapeutic target in HCC.

Our findings also revealed that FTI-277, a farnesyltransferase inhibitor, had a better curative effect in high-risk patients, while MK-2206, an Akt allosteric inhibitor, had a superior therapeutic effect in low-risk patients. The real-time PCR results uncovered the RNA expression of AC005062.1 in all the three PAAD cell lines was elevated several thousandfold. In conclusion, our URGs-based classification panel could be triumphantly served as a prediction tool for survival evaluation in patients with PAAD, and the genes in this panel could be developed as a potential target in PAAD therapy.

In the coculture assay, the AKT inhibitor MK2206 significantly recovered CLDN1 expression downregulated by WNT7A, resulting in OSCC cell migration suppression. These results suggest that CAFs stimulate OSCC cells to produce WNT7A, following CLDN1 expression downregulation by activating AKT signaling, promoting cancer cell migration. These findings highlight the importance of molecular therapies targeting the TME in OSCC.

The compound, MK-2206, an inhibitor of the protein kinases AKT1/2/3, is undergoing evaluation in multiple clinical trials for the treatment of certain types of cancers, including those resistant to erlotinib...Methodology: The efficacy of MK-2206 (0.03-1 μM), in combination with the ABCB1 transporter sub-strates doxorubicin and paclitaxel, and ABCG2 transporter substrates mitoxantrone, SN-38 and topotecan, were determined in the cancer cell lines, KB-C2 and SW620/Ad300, which overexpress the ABCB1 transporter or H460/MX20 and S1-M1-80, which overexpress the ABCG2 transporter, respectively... These in vitro data indicated that MK-2206 surmounts resistance to mitoxantrone, SN-38 and topotecan in cancer cells overexpressing the ABCG2 transporter. If these results can be translated to humans, it is possible that MK-2206 could be used to surmount MDR in cancer cells overexpressing the ABCG2 transporter.

A specific Akt inhibitor, MK2206, reduced the cell viability, Akt and GSK3β phosphorylation, and HO-1 and NRF2 expression in U251 cells exposed to rotenone...Together, these findings demonstrate that the heterozygous knockout of LAR in astrocytes can play a key role in protecting both astrocytic cells and cocultured neurons in a rotenone-induced cell-based model of PD. This neuroprotective effect is attributable to the augmentation of IGF1R-Akt-GDNF signaling and the maintenance of astrocytic mitochondrial function.

Reducing YTHDC1 expression activated DNA damage response, which includes quicker cell cycle recovery, apoptosis evasion and an enhanced DNA repair capability, whereas these effects were attenuated when MK2206, a PI3K/AKT inhibitor was applied. We provide novel evidence that PTEN/PI3K/AKT signalling pathway could be regulated by YTHDC1 in an m A-dependent manner and highlight a critical role of YTHDC1 in cisplatin resistance of bladder cancer.

We found that patients in stemness subgroup I had a poor prognosis and benefited from nilotinib, MK-2206 and axitinib treatment. Overall, we established a novel stemness classification using the mRNAsi score and eight stemness-related genes that may be biomarkers. Clinical decision-making should be guided by this new signature in prospective studies.

The effects of HDGF on promoting the gefitinib resistance were largely attenuated by MK2206 (Akt inhibitor) or U0126 (ERK inhibitor). In summary, HDGF contributes to gefitinib resistance by activating the Akt and ERK signaling pathways. The higher HDGF levels may predict poor efficacy for TKI treatment, thus it has the potential to serve as a new target for overcoming tyrosine kinase inhibitor resistance in combating NSCLC.