PIK-75

The combined use of palbociclib and PIK75 synergistically inhibited the expression of the cell cycle proteins CCNE1, CDC6, and CDC25A, as well as the abnormal activation of PIK3CA and AKT phosphorylation. The combination of these two drugs synergistically inhibited tumor cell cycle progression and promoted apoptosis in vitro and in vivo, which provides a promising idea for the treatment of ESCC in the future.

Quantitative high-throughput drug combination screening identified potent synergy between phosphatidylinositol-3-kinase (PI3K) inhibitor, PIK75 and heat shock protein 90 (HSP90) inhibitors, Ganetespib (STA9090), HSP990, or Luminespib (NVP-AUY922). Further antitumor efficacy was confirmed by the BGT226-STA9090 combination in human ACC xenograft model and five PDOs with different pathogenic mutations. Conclusively, the combinations of PI3K and HSP90 inhibitors were highly effective in preclinical studies, warranting a clinical trial in patients with advanced ACC.

Additionally, we found that PIK-75 oc-HDL NP, but not free PIK-75 or oc-HDL NP alone, reduced the IC50 in the NCI-60 cell line panel and additional pancreatic cancer cell lines. These data demonstrate the first example of drug-loaded oc-HDL NP that actively target SR-B1 and kill cancer cells in vitro and in vivo, encouraging further development and translation to human patients.

UWG02CTCs were highly responsive to the PI3K p110α-subunit targeted drugs PIK-75 (IC50 = 37.0 ± 11.1 nM) or alpelisib (7.05 ± 3.7 µM). PIK-75 plus gefitinib significantly impaired UWG02CTC invasion in an organotypic assay. In conclusion, UWG02CTCs are a powerful ex vivo mGAC drug responsiveness model revealing EGFR/PI3K-targeted drugs as a promising combination treatment option for HER2-negative, RAS wild-type mGAC patients.

This study investigates the potential of targeted inhibition of the p110α-subunit of PI3K with PIK-75 or BGT226 (P13Ki), and of CDK1/2/5/9 with dinaciclib (CDKi) as single agents and in combination. The differential responses between the cell lines correlated with driver gene mutation profiles. These findings suggest that personalised medicine approaches targeting PI3K and CDK pathways in combination may yield some benefit for mcSCC, and that more complex 3D models should be considered for drug responsiveness studies in this disease.

Preclinical in vitro studies were performed to validate the efficacy of HSP90 inhibitors (STA9090, AUY922, HSP990), with PI3K inhibitors; PIK75 (investigational) or clinically available BGT226, and their pairwise combinations, in NCI-H295R and SW13 ACC cells. Conclusively, combination of HSP90 and PI3K inhibitors demonstrated a promising in vitro synergistic efficacy by inhibiting the key oncogenic targets of ACC. Further validation of in vivo efficacy is warranted.

TAL1-positive, AKT-activated T-ALL cells were very sensitive to PIK-75, as evidenced by the growth inhibition and apoptosis induction, while T-ALL cells that exhibited activation of the JAK-STAT pathway were insensitive to this drug. Together, our study demonstrates a strategy targeting two types of core machineries mediated by oncogenic transcription factors and signaling pathways in T-ALL.

Furthermore, PIK-75 treatment is efficacious in overcoming primary and acquired venetoclax resistance in xenograft models and inhibited tumor cell dissemination to spleen in mice. Altogether, our data demonstrated that PIK-75 is highly potent in overcoming primary, acquired, or stromal cells-induced venetoclax resistances in MCL cells and revealed a new tumor vulnerability that can be exploited clinically in difficult to treat MCL cases, especially those with venetoclax resistance.

Simultaneously constructed and analyzed differentially expressed cellular networks presented in this study, revealed distinct consequences of isoform specific PI3K inhibition in PTEN adequate and deficient liver cancer cells. We demonstrated the importance of context dependent and isoform specific PI3K/Akt/mTOR signaling inhibition in drug resistance during combination therapies. ( https://github.com/cansyl/Isoform-spesific-PI3K-inhibitor-analysis ).