MK-2206

This study defines an oncogenic axis wherein ELYS promotes HCC stemness and metastasis by activating PI3K/AKT, triggering a FOXO6-NUP205 cascade to drive Hedgehog, representing a pivotal mechanism and therapeutic target.

Commercial cell lines showed promising viability reduction similar to prior laboratory results with treatments, including 5-μM darovasertib, 700-nM selumetinib, 700-nM selumetinib + 1000-nM MK-2206, 500-nM sotrastaurin + 1000-nM alpelisib, and 100-nM trametinib, with overall viability reduced to 32.5% for all drugs. PDLs and PDOs may more accurately represent uveal melanoma clinical response. Demonstrating efficacy of novel therapeutics in these models could improve the likelihood of successful translation for future clinical trials, but future studies are needed to define clinically meaningful in-vitro response thresholds.

P2, N=108, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Mar 2026 --> Mar 2027

Critically, knockdown of TPX2 or treatment with either the AKT pathway inhibitor MK-2206 2HCl or the glycolysis inhibitor AZ33 effectively reversed the promoting effects of CDT1 on AKT pathway activity, glycolytic metabolism, and tumour progression in CDT1-overexpressing NSCLC cells. Collectively, this study elucidates that CDT1 and E2F1 mutually promote the glycolysis and progression of NSCLC cells by activating the TPX2/AKT pathway. These findings provide novel therapeutic targets for refractory NSCLC treatment.

P1, N=62, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Mar 2026 --> Mar 2027

Indirubin exerts broad anti-ovarian cancer effects by inhibiting proliferation, migration, invasion as well as EMT, with demonstrated efficacy in xenograft models and no observed organ toxicity. Its mechanistic overlap with PI3K/AKT inhibitors underscores its potential as a multitargeted therapeutic agent.

GK may serve as a potential therapeutic candidate for UV-induced photoaging by virtue of its dual capacity to scavenge ROS and enhance AKT-mediated DNA repair.

The results suggest that latent improved outcome of high-risk BCR patients (mean PSA doubling time 4.4 months) on combined MK-2206+Bic versus Bic alone was attributable to a subgroup identified by crosstalk AR activation secondary to inhibition of AKT. Toxicity may affect tolerance of sustained AKT-AR inhibition.

In addition, AKR1C3 overexpression promoted aerobic glycolysis in HSCs by activating the AKT/mTOR pathway, but these effects were partly reversed by glycolysis inhibitors (2-DG) and AKT inhibitors (MK-2206). Our findings revealed the mechanism by which AKR1C3 promotes LF, suggesting that AKR1C3 may serve as a potential therapeutic target for LF, warranting further studies.

Additionally, wt-EGFR and pAKTSer473 protein complex formation in A549 cells was disrupted with an AKT inhibitor (MK2206), resulting in enhanced cytotoxicity in vitro. Our study demonstrates that EGFR-TKI response in wt-EGFR cells is dictated by BRG1 status. These findings propose screening of wt-EGFR NSCLC patients for BRG1 status for identifying individuals likely to benefit from EGFR-TKI therapy versus patients who will benefit from AKT inhibitor treatment.

Considering the metabolism of icariin into icaritin in vivo, icaritin was selected for in vitro study. Furthermore, MK2206 upregulated the expression levels of cleaved caspase-3 and p-p53(Ser15), as well as the Bax/Bcl-2 ratio, and downregulated the expression levels of p-Akt(Ser473) and p-MDM2(Ser166). These findings suggest that icariin protects against high-fat diet-induced spermatogonium apoptosis potentially through regulation of Akt/MDM2/p53 signaling and promotion of mitochondrial fusion.

MK-2206 and rapamycin suppressed the expression of ASS1 in H446-BR cell. In xenograft model, BCT-100 has little anti-tumor effect on H446-BR compared with H446 as well as H446-BR silenced sestrin3. Collectively, these results elucidate SESN3 plays an essential role in resistant mechanism, which will provide a valuable source of information for translational research.