To gain insights into PI3K/mTOR pathway dysregulation in this context, we perform a human genome-wide CRISPR/Cas9 screen for hits that synergistically blocked EBVaGC proliferation together with the PI3K antagonist alpelisib...Rather than perturbing mTORC1 lysosomal recruitment, ZMYND19 and MKLN1 block the interaction between mTORC1 and Rheb and also with mTORC1 substrates S6 and 4E-BP1. Thus, CTLH enables cells to rapidly tune mTORC1 activity at the lysosomal membrane via the ubiquitin/proteasome pathway.

P=N/A, N=600, Completed, Novartis Pharmaceuticals | Recruiting --> Completed | N=200 --> 600 | Trial completion date: Sep 2025 --> Feb 2025 | Trial primary completion date: Sep 2025 --> Feb 2025

To address this, we developed a TME-responsive polymeric micelle co-delivering alpelisib (a pan-PI3K inhibitor) and cobomarsen (a miR-155-5p inhibitor) for targeted therapy. This dual-targeting strategy effectively suppressed PIK3CA-mutated tumor growth and epithelial-mesenchymal transition. These findings reveal the role of MDSC-driven metastatic potential via the exosomal miR-155-5p/SIRT1 axis in HR + breast cancer and present a novel nanotherapeutic approach for precision intervention.

CDK4/6 inhibitors (such as palbociclib and ribociclib) block the transition from the G1 to S phase of the cell cycle and have become standard treatment for hormone receptor-positive breast cancer. It covers molecular mechanisms, synergistic effects, resistance strategies, biomarkers, and future directions, with an emphasis on immunological implications. The scope is limited to HR+/HER2-negative subtypes, excluding other cancers or non-PI3K-targeted therapies, to provide a focused foundation for translational immunology in oncology.

Application to patient samples validated the method's clinical relevance, with measured concentrations aligning with the expected ones. This is the first capillary electrophoresis method for ALP in biological matrices and the only method for simultaneous TDM of ALP and FUL, offering a robust, cost-effective, and eco-friendly alternative to traditional chromatographic approaches.

Crucially, A32 (50 mg/kg) markedly reduced hyperglycemia risk versus alpelisib and displayed favorable pharmacokinetics. These findings establish A32 as a potent, selective, and metabolically safe PI3Kα inhibitor with a promising therapeutic profile.

Copa/R had a favorable safety profile with a signal of efficacy supporting future studies of PARPi with PI3Ki.

P2, N=60, Recruiting, Hoffmann-La Roche | Trial primary completion date: Mar 2027 --> Jul 2027

P3, N=450, Recruiting, Hoffmann-La Roche | Trial primary completion date: Jan 2028 --> May 2032

Treatment with PI3K inhibitor alpelisib eradicates resistant cells in vitro and in vivo, with prolonged survival of leukemic mice through downregulation of F2R, ITGA2, and COL6A1. Thus, the lncRNA-m6A-PI3K cascade represents a new non-genetic predictor for drug resistance and poorer prognosis in cancer, and a pan-cancer mechanism underlying TKI resistance.

The PI3K inhibitors GDC-0032 and INK1117 for PI3K-α and AZD8186 for PI3K-β are now being studied in clinical trials. Research on the clinical development, therapeutic utility, and structural insights of new PI3K inhibitors is the main emphasis of this review. The inhibitors have been shown promising anticancer activity relationships.

Recent studies have shown that alpelisib, a PI3Kα inhibitor initially designed for breast cancer, is also effective at treating PROS...In unrelated disorders indeed, PI3Kα involvement has been reported in various cell types such as mesangial, tubular and immune cells. This review aims at summarizing the available evidence on the involvement of the pathway in monogenic disorders and kidney disease, highlighting PI3Kα as a potential novel therapeutic target in various nephropathies.