afuresertib (LAE002)

To study resistance mechanisms, we developed the organoid drug resistance assay (ODR-test) with patient-derived organoids from our ovarian cancer biobank and identified sustained phenotypic reprogramming and cellular plasticity of organoids under carboplatin pressure as a conserved mechanism irrespective of the basal resistance level. Additionally, we found that KRT17 expression status (K-score) is a significant negative prognostic histopathological biomarker in a large cohort (N = 384) of patients with advanced HGSOC. In organoids, increased KRT17 levels enhanced sensitivity to PI3K/Akt inhibitors alpelisib and afuresertib, highlighting the potential of KRT17 as a stratification biomarker for targeted therapies.

P1/2, N=22, Completed, Laekna Limited | Active, not recruiting --> Completed

Riz1 knockout mice (KO) were randomly treated with either the AKT inhibitor afuresertib or the mTOR inhibitor rapamycin. Mice treated with the inhibitors exhibited significantly suppressed AKT/mTOR signaling pathway in liver, muscle, and adipose tissues, as well as downregulation of genes associated with energy and lipid metabolism (L-Fabp, Pparα/γ, Ubiad1, Cyp4a12). These findings demonstrate that inhibition of either the AKT or mTOR molecules mitigates obesity and metabolic dysregulation in Riz1-/- mice, highlighting the critical role of the RIZ1/AKT/mTOR axis in maintaining metabolic homeostasis.

Drug sensitivity analysis indicated increased responsiveness of high-risk patients to agents such as Afuresertib and Venetoclax. The findings contribute to a more comprehensive understanding of the disease and provide a foundation for future clinical applications. Nevertheless, further large-scale validation is required to confirm these findings and enhance their clinical utility.

We revealed a positive correlation between the Nscore and macrophage M1, suggesting potential drug response mechanisms. Based on the identified AML subtypes and their distinct mutational landscapes, we predicted potential treatment options, with Paclitaxel, Afuresertib, and Mitoxantrone emerging as potential therapeutic agents for the AML subtypes.

Pan-cancer samples suggested that high RHEBL1 expression facilitates TAM infiltration and is correlated with tumour immunosuppressive status (TCGA). High expression of RHEBL1 may benefit from the therapy of 5-FU, ABT737, Afuresertib, AGI-5198, AGI-6780, and Alisertib.

The addition of afuresertib to paclitaxel did not significantly improve PFS/OS in patients with PROC. However, exploratory biomarker findings suggest potential efficacy in phospho-AKT positive patients, warranting further investigation. The safety/tolerability profile of A + P was consistent with prior AKT-inhibitor studies.

ANLN plays a crucial role in ATC progression by activating the RhoA/PI3K/AKT pathway, suggesting its potential as a therapeutic target in ATC.

Additive and/or synergistic effects were observed with alpelisib or inavolisib or copanlisib in combination with a RAS/MEK/ERK pathway inhibitor, either selumetinib (MEK), ravoxertinib (ERK 1/2), or tovorafenib (DAY101, RAF). Combinations of each of these three PI3K inhibitors with the KRAS mutation specific inhibitors MTRX1133 (KRAS G12D) or sotorasib (KRAS G12C) had selective activity in cell lines harboring the corresponding target. Lastly, combination effects were observed from vertical inhibition of the PI3K/AKT/mTOR pathway with a PI3K inhibitor in combination with either the mTORC1/2 inhibitor sapanisertib or an AKT inhibitor, ipatasertib or afuresertib.

ANLN plays a crucial role in ATC progression by activating the RhoA/PI3K/AKT pathway, suggesting its potential as a therapeutic target in ATC.

Treatment of cells with the AKT inhibitors MK2206 and GSK2110183 revealed that the PRKAA1 overexpression group was less sensitive to AKT inhibitors than the negative control group. Taken together, PRKAA1 can be used as a potential prognostic marker and new target for tumor immunotherapy.

P1/2, N=22, Active, not recruiting, Laekna Limited | Recruiting --> Active, not recruiting | N=167 --> 22