dactolisib (RTB101)

To investigate cellular responses, the glycolytic inhibitor 2-deoxy-D-glucose (2-DG) was administered to the cells...The increase in glycolysis levels following IDH2 mutation may contribute to the reduced efficacy of Enasidenib in inhibiting the proliferation of IDH-mutant AML cells...BEZ235 significantly inhibits the expression of phosphorylated PI3K (p-PI3K), phosphorylated Akt (p-Akt), mTOR, glycolytic metabolism, and Ara-C resistance both in vitro and in vivo. Overexpression and mutation of IDH2 coordinate with the Warburg effect through the PI3K/Akt/mTOR pathway to promote Ara-C resistance in AML.

Moreover, A549 and H460 cells treated with both combinations demonstrated augmented caspase-3 levels, implying substantial apoptotic activity. Altogether, these results accentuated the prospective implementation of sericin in combination with dactolisib and vitamin D at low doses to preclude lung cancer cell proliferation.

Here, we conducted a study of the metabolic and signaling implications associated with autophagy induced by glutamine (Gln) and serum starvation and PI3K/mTOR inhibitor and autophagy inducer NVP-BEZ235 (BEZ) in the head and neck squamous cell carcinoma (HNSCC) cell line FaDu...We also found that alterations in the release of inflammatory cytokines constitute a principal response to autophagy induction. Importantly, the specific mechanism driving autophagy induction significantly influenced the composition of the EVs-associated cytokine secretome.

Our candidate approach identifies FOXN3-AS1 as a prognostic indicator of survival in AML with a potential immune-related role. The preliminary observations we made on FOXN3-AS1/DNMT1 crosstalk warrant more in-depth invested immunotherapeutic approaches in AML.

Compounds 3b and 3e were further evaluated for their in vitro inhibitory activities against PI3Kα and mTOR compared to alpelisib and dactolisib, respectively as reference drugs. Molecular docking experiments provided additional explanation for these results by demonstrating the ability of these derivatives to form a network of key interactions, known to be essential for PI3Kα/mTOR inhibitors. All these experimental results suggested that 3b and 3e are potential PI3Kα/mTOR dual inhibitors and could be considered promising lead compounds for the development of anticancer agents.

Furthermore, trametinib and BEZ-235 synergistically downregulated the expression of related proteins in the MAPK and PI3K/AKT/mTOR pathways, and decreased glucose consumption and lactic acid production through suppressing the expressions of glucose transporter 1 (GLUT1) and lactate dehydrogenase A (LDHA). These data imply that simultaneous inhibition of the MAPK and PI3K/AKT/mTOR pathways using trametinib combined with BEZ-235 could synergistically impair glucose metabolism, resulting in an obvious synergistic therapeutic effect against NSCLC.

Taken together, our results indicate PKCί/PI3K/AKT/mTOR signalling cascade could be a novel therapeutic target in a lethal pathology like HGSOC.

Importantly, the BRAF/RAF1 inhibitor naporafenib, the MEK inhibitor trametinib and the ERK inhibitor ulixertinib failed to reduce pT401 levels in these settings, supporting an alternative ERK-independent pathway to T401 phosphorylation...Conversely, genetic mTOR pathway activation by oncogenic RHEB (Q64L) and mTOR (S2215Y and R2505P) mutants substantially increased pT401, an effect that was reverted by dactolisib and torin1 but not by trametinib...Using mass spectrometry, we provide further evidence that torin1 suppresses the phosphorylation of T401, S405 and S409 but not of other important regulatory phosphorylation sites such as S446, S729 and S750. In summary, our data identify the mTOR axis and its inhibitors of (pre)clinical relevance as novel modulators of BRAF phosphorylation at T401.

The combination of the two drugs inhibited the phosphorylation of PI3K, Akt, and Erk in the PI3K/mTOR and MAPK pathway, i.e., BEZ235 enhanced the BMS-1166 treatment effect by blocking the PI3K/mTOR pathway and interfering with the crosstalk of the MAPK pathway. Therefore, these findings provide a theoretical basis for BMS-1166 combined with BEZ235 in the trial treatment of colorectal cancer.

Similar results regarding the interaction between p62 and CDK4 were observed in the NVP-BEZ235 treated NB xenograft mouse model. Autophagic degradation of CDK4 plays a pivotal role in G0/G1 cell cycle arrest in NB cells treated with NVP-BEZ235.

More interestingly, Survivin inhibition reactivated the Akt/FoxO3a pathway and elevated SIRT6 levels, establishing a positive feedback loop. Our results identify Survivin as a novel downstream transcriptional target of SIRT6 that fosters tumor growth and holds promise as a prospective target for colon cancer therapy.

GSCs play a complex role in mediating radioresistance and chemoresistance, emphasizing the necessity for precision therapies that consider the heterogeneity within the GSC population and the dynamic tumor microenvironment to enhance outcomes for glioblastoma patients.

AST IV has a potential anti-AS effect, which can improve the pathological changes of the aorta in ApoE-/- rats fed with a high-fat diet, reduce the level of inflammatory factors, and modulate the composition of intestinal flora via the PI3K/Akt/mTOR pathway.

Mechanistically, by blocking PI3K/AKT/mTOR pathway with BEZ235, the effects of SETD5 overexpression on cell viability and Nanog and Sox2 protein expression were reversed. Our results substantiated that SETD5 functioned as an oncogene by promoting cell growth and stemness in colorectal cancer cells through activating the PI3K/AKT/mTOR signaling pathway.

We administered a combination therapy of phosphoinositide 3-kinase/mammalian target of rapamycin (PI3K/mTOR) dual inhibitor BEZ235 and Lactobacillus rhamnosus HN001 to primary liver cancer model mice with cardiac allografts...We also found that this phenomenon was accompanied by the regulation of inflammatory IL-6 expression. Our study presents a novel and effective therapeutic approach to address antitumor immunity and prevent allograft rejection.

Specifically, photosensitizer zinc phthalocyanine (ZnPc) and PI3K/mTOR inhibitor BEZ235 (BEZ) were co-loaded into PLS which was constructed by click chemistry conjugating MEK inhibitor selumetinib (SEL) to low molecular weight heparin with ROS-responsive oxalate bond. As a result, PDT was dramatically promoted through glycolysis-non-canonical glutamine dual-metabolism regulation, achieving complete elimination of tumors in vivo. Above all, this study achieved effective multidimensional metabolic modulation based on integrated smart nanodrug delivery, helping overcome the therapeutic challenges posed by KRAS mutations of PDAC.

Furthermore, we predicted and experimentally validated drugs targeting ESCC EMT, including dactolisib, docetaxel, and nutlin, which demonstrated efficacy in inhibiting EMT and metastasis in ESCC. Through the integration of scRNA-seq, RNA-seq, and TCGA data with experimental validation, our comprehensive analysis elucidated the landscape of EMT during the entire course of ESCC development and metastasis. These findings provide valuable insights and a reference for refining ESCC clinical treatment strategies.

Drug sensitivity analysis demonstrated positive correlations between F2R and several drugs, including BEZ235, CGP-60474, Dasatinib, HG-6-64-1, Aazopanib, Rapamycin, Sunitinib and TGX221, while negative correlation with CP724714, FH535, GSK1904529A, JNK-9L, LY317615, pyrimidine, rTRAIL and Vinorelbine. In conclusion, this study underscores the significance of F2R as a potential biomarker in gastric adenocarcinoma, shedding light on its molecular mechanisms in tumorigenesis. F2R holds promise for aiding in the diagnosis, prognosis, and targeted therapy of STAD.

In these experiments, we found that low doses shikonin and dual PI3K-mTOR inhibitor (BEZ235) have a synergistic effect that inhibits the spheroid formation from chemoresistant lung cancer sublines. Inhibiting the proliferation of lung cancer stem cells is believed to reduce the recurrence of lung cancer; therefore, shikonin's anti-drug resistance and anti-cancer stem cell activities make it a highly interesting molecule for future combined lung cancer therapy.

The mTOR inhibitor dactolisib and FAO inhibitor perhexiline exert a synergistic effect on CLL cells...In summary, circTET2 plays an important role in the modulation of lipid metabolism and cell proliferation in CLL. This study demonstrates the clinical value of circTET2 as a prognostic indicator as well as provides novel insights in targeting treatment for CLL.

Moreover, qRT-PCR results showed a significant increase in caspase 3, caspase 7, Bax and p53 genes, while a decrease in Bcl-2 gene expression levels. These findings suggest that combination therapy of NVP-BEZ235 and curcumin may be a promising therapeutic candidate for treatment of neuroblastoma.

Taken together, we indicated that the combinational therapy with BEZ235 and R848 could be considered as a potential and powerful therapeutic option for AML patients. Further clinical studies are required to expand our current findings.

Our findings reveal that active XBP1 prevents the cytotoxic effects of a dual PI3K/mTOR pathway inhibitor (BEZ235) in pre-B NRAS ALL cells. This implies targeting XBP1 in combination with BEZ235 as a promising new targeted strategy against the oncogenic RAS in NRAS -mutated pre-B ALL.

PI3K/AKT/mTOR signaling activator, insulin, enhanced SCLC radioresistance, while the synergistic effect of BEZ235/GSK2126458 and IR can be attenuated by N-acetylcysteine, and enhanced by 6-amino niacinamide. GEMM and allograft transplantation assays further confirmed their synergistic effect in vivo. This study provided insights into the connection between PI3K/AKT/mTOR signaling and the PPP underlying radioresistance and provided evidence of mechanisms supporting PI3K/mTOR inhibitors as possible therapeutic strategies to abrogate SCLC radioresistance.

This subtype tended to metastasize and was resistant to respond to immunotherapy. Pharmacogenomics analysis showed three therapeutic agents (NVP-BEZ235, LY2606368, and rutin) were potential interventions for MNG-4.

It is possible that FAP could be a reliable biomarker for the diagnosis and prognosis of ccRCC because of its role in the ccRCC progression via triggering the PI3K/AKT/mTOR signaling pathway.

The impact of Dactolisib, a dual PI3K/mTOR inhibitor, and Lys05, a dimeric chloroquine, was tested on the survival of breast cancer MCF-7 and lung cancer A549 cells. A549 cells treated in a 2:1 ratio of Lys05 and Dactolisib demonstrated a synergistic effect on cell death, proliferation, and apoptotic gene markers, in addition to its effect on autophagic gene and protein markers, showing an enhanced effect compared to monotherapy. Therefore, the PI3K/AKT kinase inhibitor/autophagy inhibitor combination establishes higher therapeutic benefits on A549 cells compared to kinase inhibitor monotherapy.

Using cell line model systems we show that treatment with the CDK4/6 inhibitor palbociclib effects dephosphorylation of the retinoblastoma protein (RB) and causes cell cycle arrest in G1 in BIA-ALCL. Consequently, CCND2 protein levels declined after stimulation with BEZ-235, RB was dephosphorylated and the cell cycle was arrested in G1. Taken together, our data imply potential application of CDK4/6 inhibitors and PI3K/AKT inhibitors for the therapy of BIA-ALCL.

We used a highly specific PI3K/mTOR inhibitor, dactolisib (NVP-BEZ235), and Mnk inhibitor - CGP57380 alone and in combination...Although when used independently, both drugs suppressed cell proliferation and migration, their combination has additional antitumor effects. We demonstrate that simultaneous inhibition of both pathways may prevent possible drug resistance.

Compared to the positive drug Dactolisib, FD274 exhibited significant anti-proliferation of AML cell lines (HL-60 and MOLM-16 with IC values of 0.092 μM and 0.084 μM, respectively) in vitro. Furthermore, FD274 demonstrated dose-dependent inhibition of tumor growth in the HL-60 xenograft model in vivo, with 91% inhibition of tumor growth at an intraperitoneal injection dose of 10 mg/kg and no observable toxicity. All of these results suggest that FD274 has potential for further development as a promising PI3K/mTOR targeted anti-AML drug candidate.

TWF1 expression was associated with tumor immune infiltration (such as dendritic cells resting, eosinophils, macrophages M0, and others), drug sensitivity (such as A-770041, Bleomycin, and BEZ235), tumor mutation burden (TMB), and sensitivity to immunotherapy. TWF1 overexpression was correlated with poor prognoses and immune status of LUAD patients. Inhibited TWF1 expression delayed the growth and migration of cancer cells by downregulating MMP protein, implying that TWF1 is a promising biomarker for the prognoses of LUAD patients.

These drugs were AZD-1208, a pan-PIM kinase inhibitor; BEZ235/Dactolisib, a pan-PI3K-mTOR dual inhibitor, a combination of both AZD-1208 and BEZ235, and AUM-302 – a preclinical PIM, PI3K, mTOR triple inhibitor. However, AZD-1208 activated PI3K cascade. MKi67 and PIM genes activity switched between different cell types in response to the different treatments, which may be compensatory.ConclusionWe conclude that pre-clinical drug development can and should be carried out not just on cancer cells but on complex models, including epithelium, stroma, and benign areas, and that when such drug screening is carried out, advanced endpoint analyses such as spatial transcriptomics are warranted, in order to properly assess both the promise and the pitfalls of drug candidates in clinically relevant settings.

In this study, we found that autophagy modulators autophinib, CPD18, EACC, bafilomycin A1 (BAFA1), 3-hydroxychloroquine (HCQ), rapamycin, NVP-BEZ235, Torin1, and starvation significantly alter the composition of the protein content of phosphatidylserine-positive EVs (PS-EVs) produced by cancer cells. The altered protein content of PS-EVs (data are available via ProteomeXchange with identifier PXD037164) also provides information about the cellular compartments and processes that are affected by the applied autophagy modulators. Video Abstract.

Early cancer treatment with dactolisib (dual PI3K/mTOR inhibitor) prevented the development of UBE2C-induced leptomeningeal metastases. Our findings reveal UBE2C as a key player in the development of metastatic brain disease and highlight PI3K/mTOR inhibition as a promising anticancer therapy to prevent late-stage metastatic brain cancer.

The following inhibitors were used: protein kinase inhibitors such as AKT-MK-2206, MEK-AS-703026, mTOR-everolimus and Torkinib, as well as dual PI3K and mTOR inhibitor-BEZ-235 and Omipalisib, and mTOR1/2-OSI-027 inhibitor in single-mode and their combinations with MEK1/2 kinase inhibitor AS-703026. There is a need for research on the search for new therapeutic strategies aimed at particular groups of patients. Effect of three generations of mTOR kinase inhibitors on caspase-3 activity, apoptosis and proliferation in melanoma cell lines.

Compared with PCa expressing the full-length PI3Kδ-L, PCa expressing PI3Kδ-S exhibits enhanced drug resistance properties, including a higher cell viability, more antiapoptotic and invasive capacities, and constitutively activated PI3K/AKT signaling, in the presence of PI3Kδ/PI3K inhibitors (Idelalisib, Seletalisib, Wortmannin, and Dactolisib). Additionally, SRSF2 has been identified as a critical splicing factor mediating exon 20 skipping in PIK3CD pre-mRNA. The inhibition of the SRSF2 activity by SRPIN340 successfully sensitizes AA PCa cells to PI3Kδ inhibitors, suggesting a novel therapeutic option for Idelalisib-resistant tumors.

P1, N=24, Completed, Goethe University | Unknown status --> Completed

EREG is the core onco-immunological biomarker of CuAS and modulates the cross-talk between VEGF and CD99 signaling in glioblastoma, and CuAS may provide support for immunotherapy and chemotherapy.

Furthermore, xanthatin-mediated pro-apoptosis in glioma cells was significantly reversed by autophagy inducers (rapamycin or Torin1), or PI3K-mTOR inhibitor NVP-BEZ235. Taken together, these findings indicate that anti-proliferation and pro-apoptosis effects of xanthatin in glioma are most likely by inhibiting autophagy via activation of PI3K-Akt-mTOR pathway, suggesting a potential therapeutic strategy against glioma.

To understand the pathway through which the G13D mutation induced the effects, we studied both RAS/ERK and PI3K/Akt pathways using specific inhibitors SCH772984 and BEZ235. Inhibition of this mutation reverses the process. Therefore, care needs be taken when employing targeted therapies to K-Ras mutations in clinics.