dactolisib (RTB101) / Adicet Bio 
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  • ||||||||||  Novel therapeutic strategies targeting MECOM rearranged AMLs discovered by unbiased drug screen (Section 19; Poster Board No: 10) -  Mar 25, 2025 - Abstract #AACR2025AACR_9163;    
    Co-treatment of mivebresib with dactolisib or LCL161 was superior than each drug alone in reducing AML burden and improving survival. These findings demonstrate promising preclinical activity of novel BETi-based combination with IAP or Bcl-xL inhibitor against AML with EVI1 overexpression.
  • ||||||||||  dactolisib (RTB101) / Adicet Bio
    Journal:  Knockdown of SETD5 Inhibits Colorectal Cancer Cell Growth and Stemness by Regulating PI3K/AKT/mTOR Pathway. (Pubmed Central) -  Mar 23, 2025   
    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.
  • ||||||||||  dactolisib (RTB101) / Adicet Bio
    Journal:  Epigenetic activation of PTEN by valproic acid inhibits PI3K/AKT signaling and Burkitt lymphoma cell growth. (Pubmed Central) -  Mar 14, 2025   
    Furthermore, compared to VPA treatment alone, the combination of VPA and the PI3K inhibitor BEZ235 led to even greater PTEN protein expression, further decreased p-AKT and p-p70S6K protein levels, and further reduced cell viability in BL cells. VPA exerts its antitumor effects in BL cells by modulating the PTEN/PI3K/AKT pathway through the inhibition of HDAC1.
  • ||||||||||  dactolisib (RTB101) / Adicet Bio
    Journal:  Carrier-Free Cisplatin-Dactolisib Nanoparticles for Enhanced Synergistic Antitumor Efficacy. (Pubmed Central) -  Mar 10, 2025   
    The inhibition of tumor migration and metastasis by CDDP-BEZ NPs was observed both in vitro and in vivo. Our data suggest that CDDP-BEZ NPs could serve as a safe and effective platform to maximize the synergy between both drugs in combating cancer, presenting a strategy to promote the therapeutic efficacy of platinum-based chemotherapeutic agents by combining them with PI3K inhibitors.
  • ||||||||||  chloroquine phosphate / Generic mfg., dactolisib (RTB101) / Adicet Bio
    Journal:  Coordinate autophagy and translation inhibition enhance cell death in melanoma. (Pubmed Central) -  Feb 19, 2025   
    We showed multiple direct and indirect interactions, indicating the overlap and interaction between the translation machinery and autophagy. These data suggest that coordinated inhibition of translation and autophagy promotes apoptosis and may be a new therapeutic model for melanoma treatment.
  • ||||||||||  dactolisib (RTB101) / Adicet Bio
    Journal:  Inhibition of Retinal Neovascularization by BEZ235: Targeting the Akt/4EBP1/Cyclin D1 Pathway in Endothelial Cells. (Pubmed Central) -  Jan 31, 2025   
    ERG and histological examination suggested that BEZ235 did not induce evident retinal or systemic toxicity at the dosage used to inhibit retinal neovascularization. BEZ235 effectively inhibits retinal neovascularization by downregulating cyclin D1 via 4EBP1 phosphorylation inhibition, highlighting its potential as a promising therapeutic agent for retinal neovascularization diseases.
  • ||||||||||  BI-3406 / Boehringer Ingelheim, dactolisib (RTB101) / Adicet Bio, MRTX0902 / BMS
    Preclinical, Journal:  Characterization of the BH1406 non-small cell lung cancer (NSCLC) cell line carrying an activating SOS1 mutation. (Pubmed Central) -  Dec 13, 2024   
    Besides BAY-293, BH1406 cells proved to be sensitive to the SOS1 inhibitors MRTX0902 and BI-3406...Additionally, the PI3K inhibitor dactolisib, the GSK-3 inhibitor BI-5521 as well as the bromodomain protein-directed PROTAC ARV-771 inhibited the growth of BH1406 cells significantly and showed synergistic interaction with BAY-293...BH1406 cells represent a novel cellular model suitable for the molecular characterization of SOS1 druggability. Such rare oncogenic driver genes are not included in standard NGS panels and need to be detected by expanded assays like WES.
  • ||||||||||  Mekinist (trametinib) / Novartis, BeiGene, dactolisib (RTB101) / Adicet Bio
    Journal:  MEK inhibitor trametinib combined with PI3K/mTOR inhibitor BEZ-235 as an effective strategy against NSCLC through impairment of glucose metabolism. (Pubmed Central) -  Nov 13, 2024   
    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.
  • ||||||||||  Cabometyx (cabozantinib tablet) / Exelixis, dactolisib (RTB101) / Adicet Bio
    Novel Machine Learning Approaches Tailored to Protein Configuration Predict Drug Vulnerabilities in Myeloid Neoplasia (Halls G-H (San Diego Convention Center)) -  Nov 6, 2024 - Abstract #ASH2024ASH_4307;    
    FLT3-TKD but not ITD showed higher sensitivity to cabozantinib while NRAS-Q61 to dactolisib (PI3K/mTOR dual inhibitor)...This algorithm was then used in our ongoing confirmatory drug screen collection that mimics real life application in a clinical setting. In summary, incorporation of protein configuration in drug response prediction might help unveiling unsuspected vulnerability profiles in MN addicted to specific gene mutations.
  • ||||||||||  dactolisib (RTB101) / Adicet Bio
    Journal:  Glutamine and serum starvation alters the ATP production, oxidative stress, and abundance of mitochondrial RNAs in extracellular vesicles produced by cancer cells. (Pubmed Central) -  Oct 29, 2024   
    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.
  • ||||||||||  Piqray (alpelisib) / Novartis, dactolisib (RTB101) / Adicet Bio
    Journal:  Design, synthesis, and biological evaluation of novel thiazole derivatives as PI3K/mTOR dual inhibitors. (Pubmed Central) -  Sep 30, 2024   
    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 PI3K?/mTOR inhibitors. All these experimental results suggested that 3b and 3e are potential PI3K?/mTOR dual inhibitors and could be considered promising lead compounds for the development of anticancer agents.
  • ||||||||||  dactolisib (RTB101) / Adicet Bio
    Journal, PD(L)-1 Biomarker, IO biomarker:  Dual PI3K/mTOR Inhibitor BEZ235 combined with BMS-1166 Promoting Apoptosis in Colorectal Cancer. (Pubmed Central) -  Aug 8, 2024   
    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.
  • ||||||||||  Identifying novel therapies from unbiased screens in AML with MECOM re-arrangement (Section 29) -  Mar 5, 2024 - Abstract #AACR2024AACR_5399;    
    Co-targeting the other identified druggable vulnerabilities from the drug screen with BETi (mTOR/PI3K with BGT-226 and dactolisib, Bcl-xL with navitoclax and A1155463, as well as CBP/p300 (with GNE781, identified through the CRISPR screen), exerted synergistic lethality in 3q26.2-r AML cells...These findings demonstrate promising preclinical activity of BETi and IAP protein or mTOR/PI3K antagonists in the cellular models of AML with EVI1 overexpression. This supports the rationale to determine in vivo efficacy of these BETi-based combinations against this therapy-resistant AML sub-type.
  • ||||||||||  everolimus / Generic mfg.
    Journal:  Everolimus-induced hyperpermeability of endothelial cells causes lung injury. (Pubmed Central) -  Jan 2, 2024   
    Consistent with in vitro data, everolimus treatment caused a visible lung-vascular barrier dysfunction, including an increase in protein in BALF and lung capillary-endothelial permeability, which was significantly attenuated by pretreatment with an inhibitor of PKC?, MLCK, and ryanodine. This study shows that everolimus induced pulmonary endothelial hyper-permeability, at least partly, in an MLC phosphorylation-mediated EC contraction which is influenced in a Ca-dependent manner and can lead to lung injury through mTOR-independent mechanisms.
  • ||||||||||  Xpovio (selinexor) / Karyopharm, Menarini, FORUS Therap, dactolisib (RTB101) / Adicet Bio
    FOXO Activators as Drugs for Osteoarthritis (Poster Hall; in person) -  Sep 23, 2023 - Abstract #ACRConvergence2023ACR_Convergence_2981;    
    In addition, cyproheptadine showed a potential as a modulator of cellular cholesterol biosynthesis, which is associated with age-related diseases including OA. Further experiments in vitro and in vivo are ongoing to clarify the detailed effects of cyproheptadine as a candidate for drug-repurposing in OA.
  • ||||||||||  dactolisib (RTB101) / Adicet Bio
    Journal:  Synergistic effect of Dactolisib/Lys05 combination on autophagy in A549 cells. (Pubmed Central) -  Sep 8, 2023   
    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.
  • ||||||||||  indisulam (E7070) / Eisai, RVT-2001 / Roivant, dactolisib (RTB101) / Adicet Bio
    m6A-modified circTET2 interacting with HNRNPC regulates fatty acid oxidation to promote the proliferation of chronic lymphocytic leukemia (Hynes Convention Center Meeting Room 302/304. Level 3 900 Boylston St., Boston, MA) -  Aug 14, 2023 - Abstract #IWCLL2023IWCLL_135;    
    CircTET2 that was upregulated in CLL was modulated by the splicing factors RBMX and YTHDC1, and that circTET2 interacted with HNRNPC, occupying a vital role in the modulation of lipid metabolism and cell proliferation of CLL. The data generated by this study collectively provide new evidence for a role and underlying mechanism for circRNAs in CLL lipid metabolism, and this may engender novel potential targets in clinical treatment.