Buparlisib

BACKGROUND: The phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling pathway is closely associated with the development and progression of lung cancer. Buparlisib (BKM‑120), a selective PI3K inhibitor, represents a novel potential therapeutic strategy for lung cancer. However, the reason for its limited initial efficacy as a monotherapy remains poorly understood. This study aims to systematically elucidate the key molecular mechanisms underlying the inefficacy of Buparlisib in lung cancer cells and to identify the core regulatory factors and signaling pathways involved. METHODS: A549 lung cancer cells served as the primary model, along with clinical lung cancer tissue samples and nude mouse subcutaneous xenograft models. Techniques including immunohistochemistry, Western blot, flow cytometry, eukaryotic elongation factor‑2 (EEF2) knockdown (short hairpin RNA targeting EEF2 [sh‑EEF2]), Cell Counting Kit‑8 cell proliferation assays, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) apoptosis analysis were used to investigate changes in the PI3K/AKT/mTOR‑EEF2 kinase (EEF2K)‑EEF2 pathway after Buparlisib treatment, to examine the relationship between reactive oxygen species (ROS) and EEF2 expression, and to evaluate the regulatory role of EEF2 in the anti‑lung‑cancer effects of Buparlisib. RESULTS: PI3K, EEF2K, and EEF2 were highly expressed in lung cancer tissues. Buparlisib effectively inhibited the activity of the PI3K/AKT/mTOR pathway in A549 cells, reduced EEF2K phosphorylation levels, and simultaneously significantly upregulated EEF2 protein expression (without altering its non‑phosphorylated state). EEF2 expression was highly sensitive to changes in ROS levels. Following EEF2 knockdown, the inhibitory effect of Buparlisib on A549 cell proliferation was significantly enhanced, and the apoptosis rate increased markedly. Animal experiments further confirmed that limiting EEF2 expression significantly improved the therapeutic efficacy of Buparlisib against lung cancer xenografts. CONCLUSION: Buparlisib regulates EEF2 through a dual mechanism: directly inhibiting the PI3K/AKT/mTOR‑EEF2K pathway, thereby activating EEF2, and inducing ROS to upregulate EEF2 expression. These combined actions enhance the anti‑apoptotic function of EEF2, thereby compromising the anti‑tumor effects of Buparlisib. This study provides a new direction for optimizing PI3K inhibitor‑based treatment strategies in clinical practice.

Hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer accounts for approximately 70% of breast cancer cases. Despite recent advances with cyclin-dependent kinase 4/6 inhibitors (CDK4/6i), resistance inevitably develops, often driven by activation of the phosphatidylinositol 3-kinase (PI3K)-AKT-mammalian target of rapamycin (mTOR) pathway. Genetic alterations such as PIK3CA mutations (present in ~ 45% of HR+/HER2- tumors), AKT1 mutations, and PTEN loss contribute to endocrine resistance and poor outcomes. This review summarizes emerging strategies targeting this pathway to overcome resistance in advanced disease. Isoform-specific PI3K inhibitors, including alpelisib and inavolisib, have demonstrated clinically meaningful progression-free survival benefits in PIK3CA-mutated populations, with inavolisib showing improved tolerability and efficacy. In contrast, pan-PI3K inhibitors such as buparlisib have been constrained by toxicity. Targeting downstream signaling, AKT inhibitors have also shown benefit: capivasertib has demonstrated clinical efficacy leading to US Food and Drug Administration approval, while ipatasertib has yielded encouraging results, particularly in tumors harboring PIK3CA, AKT1, or PTEN alterations. Mammalian target of rapamycin inhibitors, notably everolimus, have shown efficacy irrespective of mutation status. The dual PI3K-mTOR inhibitor (gedatolisib) has also shown promising progression-free survival benefit in a PIK3CA wild-type population. Next-generation agents, including mutant-selective PI3Kα inhibitors and bi-steric mTOR complex 1 inhibitors, are under active investigation. Optimal sequencing of these agents alongside endocrine therapy and CDK4/6i options remain a critical question, as does integration of genomic testing to guide therapy. Future directions include rational combination strategies, improved biomarker-driven selection, and novel modalities such as proteolysis-targeting chimeras (PROTACs). Collectively, these advances aim to enhance durability of response, minimize toxicity, and improve survival in HR+/HER2- metastatic breast cancer.