PIK-75

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 ).

Multiple PI3K and CDK inhibitors were found to potently inhibit cell line viability, notably the PI3K inhibitors PIK-75 & BGT226, as well as the CDK inhibitor Dinaciclib. Combination PI3K/CDK inhibitors had a profound impact upon metastatic cSCC. Such treatment may alleviate mechanisms of resistance in vivo, although response may be reliant upon the individual mutational status of the patient.

Among 1278 significantly correlated gene-drug pairs, copy number of GNA13 and DNA damage response genes CBL, DNMT3A, and PPM1D were most significantly correlated with cytotoxicity; the drugs most commonly associated with these genes were PI3K/mTOR inhibitor PIK-75, and CDK inhibitors P276-00, SNS-032, AT7519, flavopiridol and dinaciclib. Together, our data defined individualized dose-dependent relationships between copy number gains of PI3K and STAT family genes particularly on 17q and susceptibility to PI3K and cell cycle agents in neuroblastoma. Integration of genomic profiling and drug screening of patient-derived models of neuroblastoma can quantitatively define copy number-dependent sensitivities to targeted inhibitors, which can guide personalized therapy for such mutationally quiet cancers.

It is key that the underlying molecular mechanisms of the taxane resistance are elucidated to drive the development of novel targeted therapies to treat chemorefractory disease.Methods : In vitro models of taxane resistance in breast cancer were developed through continuous exposure of MDA-MB-231 and MCF7 cell lines to either paclitaxel or docetaxel...PI3K inhibitors BKM-120 and PIK-75 were identified as part of a small molecule kinase screen and found to inhibit cell growth in both taxane sensitive and resistant cell lines.Table 1: Sensitivity of taxane resistant cell lines models to BKM-120 and PIK-75 Candidate resistance-associated pathways were identified by differential gene expression analysis and proteomic analysis by RPPA... Candidate resistance-associated pathways were identified by differential gene expression analysis and proteomic analysis by RPPA. Western blotting confirmed alterations in the PI3K/Akt and MAPK pathways. PI3K inhibitors were found to have potent activity against the taxane resistant cell line models.