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  • ||||||||||  Journal:  Bipartite binding and partial inhibition links DEPTOR and mTOR in a mutually antagonistic embrace. (Pubmed Central) -  Oct 29, 2021   
    Structural analyses of the mTORC1/DEPTOR complex showed DEPTOR's PDZ domain interacting with the mTOR FAT region, and the unstructured linker preceding the PDZ binding to the mTOR FRB domain. The linker and PDZ form the minimal inhibitory unit, but the N-terminal tandem DEP domains also significantly contribute to inhibition.
  • ||||||||||  Preclinical, Journal:  Acupuncture improves cognitive function of vascular dementia rats by regulating PI3K/Akt/mTOR pathway (Pubmed Central) -  Oct 28, 2021   
    Our data demonstrate that CAP can protect against LPS-induced ALI by inhibiting oxidative stress, inflammatory responses and apoptosis through down-regulation of the HMGB1/NF-κB and PI3K/AKT/mTOR pathways. Acupuncture can improve cognitive function of VD rats, which may be related with its functions in easing oxidative stress and MMP reduction by activating PI3K/Akt/mTOR signaling pathway in the hippocampus.
  • ||||||||||  Journal, IO biomarker:  Curcumol inhibits lung adenocarcinoma growth and metastasis via inactivation of PI3K/AKT and Wnt/ß-catenin pathway. (Pubmed Central) -  Oct 28, 2021   
    In addition, lung metastasis model experiment suggested that Cur dramatically decreased the ratio of lung/total weight, tumor metastatic nodules, and the expressions of MMP-2 and MMP-9 in lung tissues compared with the control. Overall, these data suggested that the inhibitory activity of Cur on lung adenocarcinoma via the inactivation of PI3K/Akt and Wnt/ ß-catenin pathways, at least in part, indicating that curcumol may be a potential anti-tumor agent for lung adenocarcinoma therapy.
  • ||||||||||  Preclinical, Journal:  Silencing of lncRNA UCA1 inhibited the pathological progression in PCOS mice through the regulation of PI3K/AKT signaling pathway. (Pubmed Central) -  Oct 28, 2021   
    All in all, our study concluded that BMSCs-derived exosomal hsa-miR-23b-3p could maintain Th17/Treg balance by targeting KLF5 through suppression of the PI3k/Akt/NF-κB signaling pathway, thus inhibit IA formation. Our study revealed that, in vitro, UCA1 knockdown influenced the apoptosis and proliferation of KGN cells, in vivo, silencing of UCA1 regulated the ovary structural damage, serum insulin release, pro-inflammatory production, and AKT signaling pathway activation, suggesting lncRNA UCA1 plays an important role in the pathological progression of PCOS.
  • ||||||||||  Review, Journal:  The PI3K/Akt Pathway: Emerging Roles in Skin Homeostasis and a Group of Non-Malignant Skin Disorders. (Pubmed Central) -  Oct 28, 2021   
    The enhanced understanding of dysfunction of PI3K/Akt pathway in patients with these non-malignant disorders has offered a solid foundation for the progress of updated therapeutic targets. This article reviews the latest advances in the roles of PI3K/Akt pathway and their targets in the skin homeostasis and progression of a wide range of non-malignant skin disorders and describes the current progress in preclinical and clinical researches on the involvement of PI3K/Akt pathway targeted therapies.
  • ||||||||||  quercetin (LY294002) / Eli Lilly
    Journal:  Cornuside I promoted osteogenic differentiation of bone mesenchymal stem cells through PI3K/Akt signaling pathway. (Pubmed Central) -  Oct 28, 2021   
    This article reviews the latest advances in the roles of PI3K/Akt pathway and their targets in the skin homeostasis and progression of a wide range of non-malignant skin disorders and describes the current progress in preclinical and clinical researches on the involvement of PI3K/Akt pathway targeted therapies. Cornuside I plays a positive role in promoting osteogenic differentiation of BMSCs, which was related with activation of PI3K/Akt signaling pathway.
  • ||||||||||  daunorubicin / Generic mfg.
    [VIRTUAL] PHARMACOLOGICAL INACTIVATION OF RAC PROTEINS INHIBITS THE PI3K/ATK/MTOR PATHWAY AND POTENTIALIZES THE EFFECTS OF DAUNORUBICIN ON ACUTE MYELOID LEUKEMIA CELLS () -  Oct 27, 2021 - Abstract #HEMO2021HEMO_1295;    
    Objectives In this study we evaluated the effects of treatment with EHT-1864, a pharmacological inhibitor of Rac1, Rac2 and Rac3, in the PI3K/AKT/mTOR pathway in OCI-AML3 leukemic lineage. The effects of the combination of EHT-1864 and daunorubicin, one of the drugs already used in the treatment of AML, were also evaluated on the survival of these same cells.Methods The expression of proteins from the PI3K/AKT/mTOR pathway was evaluated by western blot in OCI cells -AML3 treated with EHT-1864 (0.5-30μM) for 48 and 72 hours. GAPDH expression was used as a normalizer. The effects of combined treatment of EHT-1864 (5μM and 10μM) with daunorubicin (1-200M) for 48 and 72 hours were evaluated on the viability and apoptosis of OCI-AML3 cells. For this, the cells were treated with the drugs alone or in combination and evaluated by MTT assay and annexin V and propidium iodide labeling followed by analysis by flow cytometry.Results Treatment with EHT-1864 inhibited the PI3K/AKT/ pathway mTOR, evidenced by reduced phosphorylation of AKT (Ser 473), mTOR (Ser 2448), EBP1 (Thr 70), PDK1, p70s6k (Ser 424 Thr 421). We also observed increased activation of PTEN (reduction of p-PTEN Ser 380). Interestingly, combined treatment of EHT-1864 and daunorubicin was significantly more effective than drug treatments alone in reducing apoptosis and reducing cell viability. Discussion Previous Results from our group have shown that treatment with EHT-1864 induces the processes of apoptosis and autophagy, as well as arrest in the cell cycle of leukemic cells. The findings of this study indicate that these effects can be at least partially explained by the inhibition of the PI3K/AKT/mTOR pathway. The potentiation of the effects of daunorubicin treatment on leukemic cells suggests that combined treatment is an interesting therapeutic option to be further explored in future studies.Conclusion Pharmacological inhibition of Rac proteins through EHT-1864 inhibited the PI3K/AKT/mTOR pathway in leukemic cells. Combined in vitro treatment of EHT-1864 and low doses of daunorubicin potentiated apoptosis of OCI-AML3 cells. Funding: FAPESP.
  • ||||||||||  Journal, IO biomarker:  Over expression of PI3K-AkT reduces apoptosis and increases prostate size in benign prostatic hyperplasia. (Pubmed Central) -  Oct 27, 2021   
    Discussion Previous Results from our group have shown that treatment with EHT-1864 induces the processes of apoptosis and autophagy, as well as arrest in the cell cycle of leukemic cells. The findings of this study indicate that these effects can be at least partially explained by the inhibition of the PI3K/AKT/mTOR pathway. The potentiation of the effects of daunorubicin treatment on leukemic cells suggests that combined treatment is an interesting therapeutic option to be further explored in future studies.Conclusion Pharmacological inhibition of Rac proteins through EHT-1864 inhibited the PI3K/AKT/mTOR pathway in leukemic cells. Combined in vitro treatment of EHT-1864 and low doses of daunorubicin potentiated apoptosis of OCI-AML3 cells. Funding: FAPESP. Overexpression of PI3K/AKT pathway and BcL-2 were associated with reduced apoptosis and increased prostate size in BPH.
  • ||||||||||  Biomarker, Clinical, Journal:  TGF-β/PI3K/AKT/mTOR/NF-kB pathway. Clinicopathological features in prostate cancer. (Pubmed Central) -  Oct 27, 2021   
    Cox multivariate analysis between the prognostic variables (pathological tumor stage, Gleason score, and node involvement) and inmunohistochemical parameters confirmed TGFBR1 and PI3K as a prognostic and independent marker of biochemical progression in prostate cancer. Our results suggest that TGFBR1 and PI3K could be used as useful biomarkers for early diagnosis and prognoses for biochemical recurrence in prostate cancer after radical prostatectomy.
  • ||||||||||  Journal:  KLK6 mediates stemness and metabolism of gastric carcinoma cells via the PI3K/AKT/mTOR signaling pathway. (Pubmed Central) -  Oct 27, 2021   
    Compared with that in the control and negative control groups, the percentage of CD133 and CD44 cells, the protein expression level of Oct-4, Nanog, HK1, HK2, GLUT1, p-PI3K, p-AKT and p-mTOR, and ATP content, lactic acid production, glucose uptake and gastric tumor volume were significantly decreased by sh-KLK6 (P<0.05), whereas KLK6 overexpression induced the opposite effect (P<0.05). In conclusion, KLK6 modulated stemness properties and cell metabolic profile in gastric carcinoma cells and the mechanism may be associated with the PI3K/AKT/mTOR signaling pathway.
  • ||||||||||  Journal:  Targeted delivery of a phosphoinositide 3-kinase γ inhibitor to restore organ function in sepsis. (Pubmed Central) -  Oct 27, 2021   
    Applying this strategy to a murine model of sepsis, we observed the PI3Kγ-dependent restoration of biliary canalicular architecture, maintained excretory liver function, and improved survival without impairing host defense mechanisms. This strategy carries the potential to expand targeted nanomedicines to disease entities with systemic inflammation and concomitantly impaired barrier functionality.
  • ||||||||||  Ibrance (palbociclib) / Pfizer
    A kinase inhibitor library screen reveals novel candidates that reverse CDK4/6 inhibitor resistance in CDK6 amplified HR(+) breast cancer (Hall 1) -  Oct 26, 2021 - Abstract #SABCS2021SABCS_1082;    
    We performed BRET (bioluminescence resonance energy transfer) and confirmed that the D224Y changed the BRET values for a palbociclib luminescent tracer, suggesting that this mutant could modulate the binding affinity of CDK4/6 inhibitors towards CDK6...We further identified the D224Y mutant as a point mutation that abolished resistance. Our findings highlight the role of CDK6 and conformational variants in modulating CDK4/6 inhibitor resistance and uncover potential pathways that could be exploited for therapeutic development for subsequent treatment.
  • ||||||||||  fulvestrant / Generic mfg.
    Genomic landscape of HER2-negative advanced or metastatic breast cancer with PIK3CA gain-of-function mutations (Hall 1) -  Oct 26, 2021 - Abstract #SABCS2021SABCS_908;    
    Across a series of comparisons between primary and metastatic samples, as well as HR+ and TNBC subtypes, we identified a number of co-mutations that occur alongside mut PIK3CA and which could be potentially exploited by targeted therapies. Future studies are needed to assess the prognostic/predictive role of these and other candidate gene alterations.
  • ||||||||||  Mekinist (trametinib) / Novartis, LY294002 / Eli Lilly
    Heterogeneity of preneoplastic breast tissues drives efficacy of therapeutic agents (Hall 1) -  Oct 26, 2021 - Abstract #SABCS2021SABCS_734;    
    Effectiveness of targeted drug therapies in this model of breast tumorigenesis correlated with deregulation of the associated pathway. This implies that accounting for heterogeneity of the preneoplastic breast and stage of tumorigenic progression will be important when considering targeted strategies for prevention.
  • ||||||||||  Piqray (alpelisib) / Novartis, Ibrance (palbociclib) / Pfizer
    Overexpressed cyclin D1 and CDK4 proteins are responsible for the resistance to CDK4/6 inhibitor in breast cancer that can be reversed by PI3K/mTOR inhibitors (Hall 1) -  Oct 26, 2021 - Abstract #SABCS2021SABCS_653;    
    The tumors from breast cancer patients who progressed after palbociclib treatment had significantly higher protein expression of Cyclin D1, CDK4, p-AKT and p-4E-BP1 than the paired samples before palbociclib treatment. In conclusion, our findings suggest that overexpressed Cyclin D1 and CDK4 proteins lead to the resistance to CDK4/6 inhibitor and PI3K/mTOR inhibitors are able to restore the sensitivity to CDK4/6 inhibitors, which provides the biomarker and rationale for the combinational use of CDK4/6 inhibitors and PI3K/mTOR inhibitors after CDK4/6 inhibitor resistance in breast cancer.
  • ||||||||||  Piqray (alpelisib) / Novartis
    Alpelisib monotherapy for PI3K-altered, pre-treated advanced breast cancer: A phase II study (Hall 1) -  Oct 26, 2021 - Abstract #SABCS2021SABCS_573;    
    Decline in the levels of PIK3CA mutations detected with ctDNA on therapy are significantly associated with clinical benefit, as are the presence of ESR1 mutations at baseline. ctDNA improves the yield of ESR1 mutation detection and warrants further study as a biomarker of alpelisib monotherapy benefit in endocrine-refractory populations.