Prompt recognition, intensive management, and drug discontinuation are critical. This is one of the first case reports to describe sustained euglycemia following severe and refractory hyperglycemia due to capivasertib therapy.

Hepatocellular carcinoma (HCC), lung adenocarcinoma (LUAD), and ovarian cancer (OC) cells with cisplatin-induced DNA damage were treated with lactate at a concentration gradient, Endothelial cell-specific molecule 1 (ESM1) shRNA, ESM1 overexpression plasmid, or the Protein Kinase B (AKT) Serine/Threonine Kinase 1 (Akt1) inhibitor LY294002. Analysis of tumor patient samples further validates the negative correlation between ESM1 and CD8+ T cell levels in cancer patients. In summary, lactate activates the Akt1-Murine Double Minute 2 (MDM2)-p53 pathway via ESM1 to suppress DDR, while the reduction of DDR-generated dsDNA inactivates the cyclic GMP-AMP synthase-Stimulator of Interferon Genes (cGAS-STING) pathway, thereby inhibiting CD8+ T cell immune infiltration.

However, PRDX4 overexpression showed opposite effects, which were partly reversed by the ferroptosis inhibitor, ferrostatin-1 and the inducer erastin. Most crucially, PRDX4 depletion-mediated inactivation of the phosphoinositide 3-kinase (PI3K)/AKT signaling pathway could be rescued by 740 Y-P (a PI3K activator), whereas PRDX4 overexpression triggered the activation of the PI3K/AKT signaling pathway, which could be reversed by the PI3K inhibitor LY294002. Collectively, the data suggest that PRXD4 suppresses ferroptosis in ESCC cells by activating the PI3K/AKT signaling pathway, suggesting that targeting PRDX4 may be a novel strategy for treating patients with ESCC.

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

P1/2, N=159, Not yet recruiting, Centro Di Riferimento Oncologico Di Aviano

P3, N=258, Active, not recruiting, AstraZeneca | Recruiting --> Active, not recruiting

P2, N=60, Active, not recruiting, Hospices Civils de Lyon | Recruiting --> Active, not recruiting

Importantly, these oncogenic effects were effectively reversed by GTSE1 knockdown or PI3K inhibition with LY294002, validating the pathway's functional significance. The MYBL2-GTSE1 axis promotes LSCC progression through PI3K/AKT-mediated metabolic reprogramming, representing a promising therapeutic target.

H3K18la enhances the malignant behavior of GC cells through activation of the POM121/PI3K/AKT pathway. These findings provide new insights into the role of histone lactylation in GC progression and suggest that targeting the H3K18la-POM121-PI3K/AKT axis may represent a potential therapeutic avenue worthy of further investigation.

P1/2, N=53, Not yet recruiting, Shanxi Province Cancer Hospital

To overcome this issue, herein, we developed a cobalt-pheophytin (CoPheo) coordination micelle chelating two chemotherapeutic agents including ONC201 and Palbociclib (Pal), yielding CoPheo-ONC201-Pal-F127. In addition, ONC201-mediated mitogen-activated protein kinase kinase (MEK) inhibition, combined with Pal-induced CDK4/6 blockade, promotes cellular senescence and remodels the tumor microenvironment. These three independent mechanisms collectively establish a mutually enhanced therapeutic strategy capable of overcoming the complex drug resistance driven by multiple downstream signaling pathways in KRAS-mutant pancreatic cancer.

P1/2, N=75, Active, not recruiting, Vaderis Therapeutics AG | Trial completion date: Dec 2025 --> Jan 2027 | Trial primary completion date: Mar 2025 --> Jan 2027