Based on our findings, the liquid biopsy analysis using the PQS panel seems to be both feasible and accurate, demonstrating a strong sensitivity in detecting mutations. This exploratory analysis of the clinical outcome associated to the mutational status of patients highlights the potential of molecular analysis on liquid biopsy for disease monitoring, although further validation with a larger patient cohort is necessary to confirm these preliminary observations.

No abstract available

These findings, supported by molecular docking scores and MM-PBSA binding energies, advocate for their potential superior inhibitory capability against the AKT1 enzyme. Nevertheless, it is crucial to validate these computational predictions through in vitro and in vivo studies to thoroughly evaluate the therapeutic potential and viability of these compounds for AKT1-targeted breast cancer treatment.

Schisandrin C effectively suppressed the proliferation and viability of A549 cells. Its mechanism was related to the inhibition of the AKT1 signaling pathway.

Furthermore, the binding orientation of FeIII-L with Topoisomerase II was found to be the most stable, with a binding energy -8.25 kcal/mol. This stability was attributed to the presence of five hydrophobic π-interactions with His759, Guanin13, Cytosin8, and Ala465, and numerous ionic interactions, which were more favorable than those of doxorubicin and etoposide for new regimens of chemotherapeutic activities against skin cancer.

Additionally, AKT1 activity affected normal metabolism in HuH-7 cells and resulted in the accumulation of reactive oxygen species, which activated MOMP and further promoted apoptosis. Our results systematically elucidate the mechanism of luteolin in inhibiting the proliferation of liver cancer cells, mainly through cell cycle arrest and apoptosis via targeting AKT1 and SRC.

The pharmacological inhibition of AKT1 phosphorylation using MK2206 effectively counteracted the proliferative effects induced by PTOV1 overexpression. The ability of PTOV1 to enhance CRC cell proliferation via modulation of the AKT1 signaling pathway establishes it as a potential therapeutic target and a promising biomarker for prognostic stratification in CRC.

P1, N=110, Recruiting, Alterome Therapeutics, Inc. | Not yet recruiting --> Recruiting

Capivasertib with fulvestrant was approved for patients whose tumors harbored PIK3CA/AKT1/PTEN alterations. Benefit-risk assessment in this subgroup was favorable based on a statistically significant and clinically meaningful improvement in PFS in the context of an acceptable safety profile including no evidence of a potential detriment in overall survival. By contrast, the benefit-risk was unfavorable in the biomarker-negative population.

P2, N=60, Not yet recruiting, Zhejiang Haichang Biotech Co., Ltd. | Initiation date: Apr 2024 --> Aug 2024

P1, N=110, Not yet recruiting, Alterome Therapeutics, Inc.

Adding ipatasertib to paclitaxel did not improve efficacy in PIK3CA/AKT1/PTEN-altered advanced TNBC. Biomarkers for benefit from PI3K/AKT pathway inhibition in TNBC remain poorly understood.

Overall, our study suggests that FAM114A1 plays a role in HCC cell proliferation and migration, involving the modulation of AKT1 expression. Furthermore, FAM114A1 impacts apoptosis, cell cycle, and EMT, contributing to HCC development. These findings highlight FAM114A1 as a potential novel therapeutic target for HCC treatment.

Molecular docking was applied to assess the interaction between the main compounds identified in the analysed olive oils and the human AKT1 protein, which is involved in the genesis of colorectal cancer. The findings revealed that lutein, oleuropein aglycone, and ligstroside aglycone had the highest binding affinity for the AKT1 protein.

Our study suggests obtaining TBx for CGP at time of de novo/recurrent diagnosis, followed by LBx for detecting acquired GA in 2nd + lines. Reflex TBx should be considered when ctDNA TF < 1%.

Additionally, the ubiquitination of AKT1 is essential for its translocation to the activated IR on the plasma membrane, where it plays a functional role in recruiting Glut4 and facilitating glucose uptake. This study uncovers the cellular components and processes involved in insulin-induced ubiquitination and activation of AKT1, providing insights and detailed strategies for manipulating AKT1.

HK1-S178 phosphorylation levels were significantly correlated with the occurrence and metastasis of different types of clinical tumors. We conclude that AKT not only regulates tumor glucose metabolism by directly phosphorylating HK1 and HK2, but also plays important roles in tumor progression, proliferation, and migration.

Molecules D1-D10 were found to have strong binding interactions and higher binding free energy values. In addition, Molecular dynamic simulation was performed to understand the conformational changes of protein-ligand complex.

To block pS6, we paired dasatinib with the S6K/AKT inhibitor M2698, which led to a marked reduction in pS6 in IDHm ICC cell lines and patient-derived organoids in vitro and substantial growth inhibition in ICC patient-derived xenografts in vivo. Together, these results elucidated the mechanism of action of dasatinib in IDHm ICC, revealed a signaling complex regulating S6K phosphorylation independent of mTOR, suggested markers for dasatinib sensitivity, and described a combination therapy for IDHm ICC that may be actionable in the clinic.

Although each TAT-pAKT1 variant significantly stimulated cell proliferation, cells transduced with TAT-pAKT1T308 grew significantly faster than with the other pAKT1 variants. The data demonstrate differential activity of the AKT1 phospho-forms in modulating downstream signaling and proliferation in human cells.

Taken together, CRC LNCs possessed greater constricted migratory and metastatic potential than SNCs due to ErbB4-Akt1-mediated lamin A/C phosphorylation and nuclear softening. These results may provide a potential treatment strategy for tumor metastasis by targeting nuclear stiffness in patients with cancer, particularly CRC.

After exposure to pDNA-melittin, there was no significant increase in transcription levels of caspase-3, caspase-8, BCRA1, BAX, Drp1, AKT1, and EPSTI1 genes in the normal non-cancerous groups. The findings provide novel opportunities for the therapeutic targeting of malignancies via melittin and the stimulation of the EPSTI1/Drp1/AKT1 signaling cascades.

Overall, our study revealed that PDZK1 acts as a novel oncogene in glioma by binding to AKT1 and maintaining the activation of the AKT/mTOR signaling pathway. Thus, PDZK1 may be a potential therapeutic target for glioma.

No abstract available

The combination of HDW and AP targets 16 key genes to impede the development of NPC, primarily by modulating AKT1 and VEGFA pathways.

AnxA6 deSUMOylation contributes to HCC progression and EMT phenotype, and the combination of AnxA6 and SENP1 is a better tumor biomarker for diagnosis of HCC grade malignancy and prognosis.

Our finding revealed that local anesthetic ropivacaine attenuated breast cancer stemness through AKT1/GGT1/NF-κB signaling pathway, suggesting the potential clinical value of ropivacaine in breast cancer treatment.

We found that treatment with cholesterol-lowering drugs such as lovastatin and simvastatin promoted cell apoptosis in all RMS lines by reducing Akt1 and Cav1 levels and increasing intracellular ROS levels...Furthermore, in combination with the chemotherapeutic agent actinomycin D, statins were effective in reducing cell survival through increased apoptosis. Taken together, our findings suggest that the molecularly linked signature formed by Akt1, Src, Cav1, and catalase may represent a prognostic determinant for identifying subgroups of RMS patients with higher probability of recurrence after radiotherapy. Furthermore, statin-induced oxidative stress could represent a treatment option to improve the success of radiotherapy.

P2, N=60, Not yet recruiting, Zhejiang Haichang Biotech Co., Ltd.

Further, MD simulation and PCA analyses showed that the phytochemicals possessed significant binding efficacy with CC protein. These results point the way for more investigation into SHPE compound's potential as CC treatment.

Treatment with the conventional drug of choice AZD5363 (a pan AKT inhibitor) enhanced cell death and diminished HK2 levels in AKT1 mutants...By affecting metabolism, inflammation, and redox homeostasis AKT1-E17K confers a survival advantage in meningioma cells. Our findings suggest that targeting AKT-HK2 cross-talk to induce ROS-dependent cell death could be exploited as novel therapeutic approach in meningiomas.

Human melanoma samples with high IMP-3 levels also showed high HMGA2, AKT1 and RELA expression. Our results show that IMP-3 enhances melanoma cell migration through the regulation of the AKT1 and RELA axis.

Additionally, the expression of PLK4 protein exhibited a positive correlation with AKT1 phosphorylation in glioma patient tissues. These findings highlight the pivotal role of PLK4-mediated phosphorylation of AKT1 in glioma tumorigenesis and dysregulation of glucose metabolism.

Unlike mitochondrial ME2, which accounts for adjusting the tricarboxylic acid (TCA) cycle, ME2fl functions as a scaffold that brings together the key glycolytic enzymes phosphofructokinase (PFKL), glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and pyruvate kinase M2 (PKM2), as well as Lactate dehydrogenase A (LDHA), to promote glycolysis in the cytosol. Thus, through phosphorylation of ME2fl, AKT1 enhances the glycolytic capacity of tumor cells in vitro and in vivo, revealing an unexpected role for subcellular translocation switching of ME2 mediated by AKT1 in the metabolic adaptation of tumor cells to growth stimuli.

Moreover, DHX9 was upregulated in tumors from PARPi-resistant BRCAm HGSOC patients, and high co-expression of DHX9 and AKT1 correlated with worse survival. Together, this study reveals an interaction between AKT1 and DHX9 that facilitates R-loop resolution and identifies combining ATRi and AKTi as a rational treatment strategy for BRCAm HGSOC irrespective of PARPi resistance status.

The average binding free energies for the Akt1-CQU, Akt1-Ipatasertib, and Akt1-Hit9 systems were - 34.44, - 63.37, and - 39.14 kJ mol, respectively. In summary, the results obtained in this investigation suggested that Hit9 with novel scaffold may be a promising lead compound for developing new Akt1 inhibitor for treatment of various cancers with Akt1 overexpressed.

The residual analysis demonstrated that allosteric and isoform-specific residues such as Trp80 and Val270 contributed the larger energy for ligand binding. The proposed integrated approach in this study might achieve a futuristic outcome when employed in a pharmaceutical scheme different from the conventional method.Communicated by Ramaswamy H. Sarma.

In human glioma samples, S100A9 expression was positively associated with CD206 expression, but negatively correlated with CD8+T lymphocyte accumulation in the TME. Our data indicated that glioma-derived S100A9 has a promising ability to manipulate non-malignant cells and promote immune evasion in the TME, providing valuable insight into the mechanism by which S100A9 participates in the progression of glioma.

Quercetin may mitigate doxorubicin-induced kidney injury in mice by regulating renal cell inflammatory factors and Raf/MEK/ERK signaling pathway through AKT1 to promote recovery of renal function.

In conclusion, CIP2A could interact with AKT1 to promote the malignant biological behaviors of OSCC cells by upregulating the GSK-3β/β-catenin pathway. These findings may provide a targeted therapy for OSCC treatment.

Of the 21 HER2-negative PDX models, DIACC3010 significantly inhibited the growth of 38%. Altogether, these results provide a path forward to validate the potential biomarkers of DIACC3010 sensitivity in GC and support clinical evaluation of DIACC3010 monotherapy and combination with trastuzumab in patients with HER2- negative and positive advanced GCs, respectively.

In summary, this is the first study to report that miR-143-3p overexpression in prostate cancer may inhibit EMT by targeting AKT1. The findings suggest miR-143-3p could be a useful diagnostic and prognostic biomarker for prostate cancer.