dactolisib (RTB101) / Adicet Bio - LARVOL DELTA

Epitranscriptomic regulation of NVP-BEZ235 resistance in ccRCC via the YTHDF3-SYNM regulatory pathway. (PubMed, Genes Genomics) - "Reversible resistance to NVP-BEZ235 in ccRCC is driven, at least in part, by an m6A-dependent YTHDF3-SYNM axis. Targeting YTHDF3 or SYNM may provide a rational strategy to overcome PI3K/mTOR inhibitor resistance in ccRCC."

Journal • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Solid Tumor • PTEN • YTHDF3

RETRACTION: The PI3K/mTOR Dual Inhibitor NVP-BEZ235 Stimulates Mutant p53 Degradation to Exert Anti-Tumor Effects on Triple-Negative Breast Cancer Cells. (PubMed, FEBS Open Bio) - "have determined that a retraction is necessary. The authors were informed of the decision to retract but did not respond to requests for comment."

Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer

BET inhibitor-based combinations targeting novel dependencies in MECOM-rearranged (r) AML. (PubMed, Leukemia) - "In a MECOM-r AML PDX model, mivebresib with dactolisib or LCL161, was superior to monotherapy or vehicle in reducing AML burden and increasing mouse survival. These findings highlight that cotreatment with BETi and PI3K/mTOR or IAP inhibitor exerts superior in vitro and in vivo efficacy in MECOM-r AML cells and support further evaluation of these BETi-based combinations."

Journal • Acute Myelogenous Leukemia • BCL2L1 • BRD4 • GATA2 • MECOM • MYC • PIK3CA • XIAP

Intrinsic resistance to RAS inhibitors is driven by dysregulation of KRAS degradation. (PubMed, Nat Commun) - "Co-inhibition of mTOR or the SLC3A2/SLC7A5 complex using dactolisib or JPH203 restores sensitivity to KRAS inhibitors in vitro and in vivo. These findings support combinatorial targeting of mTOR signaling or amino acid transport to overcome intrinsic resistance in KRAS-mutant lung cancer."

Journal • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • HIF1A • KRAS • LZTR1 • SLC3A2 • SLC7A5

Extracellular Vesicles Released From Prostate Cancer Cells Confer Pro-Tumor Properties to Adipocytes by Stimulating Lipolysis. (PubMed, Biofactors) - "Mechanistically, FFAs were found to trigger Akt activation, and pharmacological inhibition of this protein by BEZ235 could successfully counteract their cancer-promoting effects. Collectively, these results support the presence of an EV-driven bidirectional interplay between PCa cells and adipocytes, which reprograms the latter toward a lipolytic, tumor-promoting phenotype."

Journal • Genetic Disorders • Genito-urinary Cancer • Obesity • Oncology • Prostate Cancer • Solid Tumor • G0S2

BH3 mimetic and dual PI3K/mTOR inhibitor attenuates gemcitabine resistance in triple-negative breast cancer. (PubMed, Med Oncol) - "Triple-Negative Breast Cancer can develop resistance to gemcitabine and overcoming this resistance is critical for effective treatment. In silico analysis using GEPIA revealed a relation between hENT1 with Mcl-1 and Bcl2. These findings reveal ABT-737 and NVP-BEZ235 attenuate MDA-MB-231GEMR cell line and show potential implication on reversing resistance in TNBC for further studies."

IO biomarker • Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • BCL2 • BCL2L1 • MCL1

Construction and validation of a disulfidptosis-related risk assessment model for prediction of prognosis, immune microenvironment, drug therapy and microbiota in patients with low grade glioma. (PubMed, Int J Surg) - "Through drug sensitivity analysis, several drugs exhibited significant correlation with risk score, and molecular docking illustrated that both dactolisib and linsitinib were capable of binding tightly with most signature genes, making them potential candidates for targeted therapeutic approaches of LGG. Thus, this model can stratify LGG patients with distinct gene expression features, immune landscape, genomic instability and microbiota features. By stratifying patients with risk score, this risk model may improve the accuracy of prognostic prediction for LGG patients, which might provide new insights into the molecular targeted therapy for individual treatment in a risk score-specific manner."

Journal • Tumor mutational burden • Brain Cancer • Glioma • Oncology • Solid Tumor • CD4 • CD8 • TMB

Drug repurposing identifies novel Wee1 kinase inhibitors for triple negative breast cancer therapeutics. (PubMed, Eur J Med Chem) - "Optimal dosing ratios of 1:1 for adavosertib-cisplatin and 1:2 for dactolisib-cisplatin were identified, underscoring effective, dose-dependent synergy in these combinations. Dactolisib and adomeglivant show promise as Wee1 kinase inhibitors in TNBC, with dactolisib exhibiting superior potency, and their synergistic potential in combination therapies, such as with cisplatin, highlighting avenues for future clinical development."

Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer

Efficacy of Combinations of Targeted Agents Against Dependencies in Mecom Rearranged AML Identified By Unbiased Chemical and CRISPR Screens (ASH 2024) - "Treatment of 3q26.2-r AML cell lines for 96-hours with ORY001 (LSD1i; 3-100 nM), RGFP966 (HDAC3i; 0.5-10 µM) or GNE-781 (CBP/p300i; 10-1000 nM) induced moderate, dose-dependent cell death, as determined by flow cytometry...Treatment of the luciferized 3q26.2-r PD AML242 model, engrafted in NSG mice, with mivebresib (0.5 mg/kg, daily 5x per week), dactolisib (20 mg/kg, daily 5x per week) or LCL161 (65 mg/kg, daily 5x per week) reduced AML burden and increased survival compared to vehicle-treated mice (p < 0.05)...These treatments resulted in reduction of EVI1 and c-Myc levels, associated with preclinical differentiation and apoptotic activity in the 3q26.2-r AML cell models. Further in vivo evaluation of the efficacy of BETi or LSD1i-based combinations against 3q26.2-r AML is warranted."

Clinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • BRD4 • CD86 • GATA2 • HDAC3 • ITGAM • MECOM • MYC • PIK3CA • XIAP

Modulating Metabolic Reprogramming By Phosphoglycerate Dehydrogenase (PHGDH) Inhibitors in Omipalisib-Refractory AML (ASH 2023) - "The OCI-AML3-R cell line was the most refractory one and showed cross-resistance to another PI3K/mTOR inhibitor dactolisib and multi-tyrosine kinase inhibitor dasatinib, in addition to omipalisib. Transcriptomic and metabolomic analyses revealed that OCI-AML3-R upregulated PPP and SSP, leading to increased nucleotide synthesis, which contribute cell growth and survival. Targeting PHGDH could significantly suppress omipalisib-refractory in AML and may have implications for future clinical trials."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • ABCB1 • ABCC1 • ABCC2 • ABCG2 • MTHFD2 • PAICS • PHGDH • PSAT1 • SHMT2

Novel Machine Learning Approaches Tailored to Protein Configuration Predict Drug Vulnerabilities in Myeloid Neoplasia (ASH 2024) - "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."

Machine learning • Hematological Malignancies • Oncology • CEBPA • DNMT3A • FLT3 • IDH1 • KRAS • NRAS • RUNX1 • SF3B1 • TET2 • WT1

Targeting Acquired Resistance to KRASG12DInhibitors: designing rationale synergistic treatments. (AACR-NCI-EORTC 2025) - "Interestingly, co-treatment of MRTX133 with MG-132 or bortezomib- potent proteasome inhibitors- or dactolisib -dual PI3K and mTOR inhibitor- increased cleaved PARP levels...Thus, drug resistant models were sensitive to dual MRTX1133 and patritumab deruxtecan inhibition...More importantly, these drug combinations were also effective in sensitive and de novo MRTX1133 resistant patient-derived organoids. Our findings emphasize the necessity to design combinatorial treatments to prevent and delay the acquisition of drug resistance in KRAS-driven cancers."

Preclinical • Colorectal Cancer • Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • CD24 • ERBB3 • KRAS • STAR

Targeting treatment-resistant Systemic Lupus Erythematosus through transcriptome-informed drug repurposing (ACR Convergence 2025) - "To guide precision repurposing, we applied a transcriptome-driven strategy to identify compounds that either mimic the molecular effects of standard therapies or reverse gene expression profiles associated with treatment resistance. Paired whole-blood transcriptomes from 31 SLE patients treated with rituximab (n=8), belimumab (n=13), or cyclophosphamide (n=10) were analyzed to define drug-specific signatures (absolute log₂FC > 0.58, p < 0.05)...Rituximab's signature aligned with mTOR blockers (everolimus, dactolisib), PI3K inhibitors (PIK-75, ZSTK474), JAK2 inhibitors (fedratinib) and agents downregulating the p38-MAPK pathway (OXA)... Our analysis delineates molecular correlates of therapeutic response and identifies candidate drugs capable of emulating molecular effects of standard SLE therapies or reversing gene expression patterns associated with treatment failure, offering a framework for drug repurposing in difficult-to-treat SLE."

IO biomarker • Immunology • Inflammatory Arthritis • Lupus • Systemic Lupus Erythematosus • BCL2 • CDC37

Predictive value of metabolic state on PanNET response to mTOR inhibitors. (PubMed, Endocr Relat Cancer) - "mTOR inhibitors such as everolimus and BEZ235 have demonstrated efficacy in pancreatic neuroendocrine tumors (PanNET) at the cost of severe side effects, and no biomarker currently predicts response. High expression of CAIX and LDHA, two markers of pseudohypoxia/glycolysis, was associated with shorter progression-free survival in patients treated with everolimus. This study demonstrates that tissue culture can effectively assess drug response in PanNET and identifies a pseudohypoxic/glycolytic profile as a determinant of resistance to mTOR inhibition, detectable by immunohistochemistry and potentially noninvasively by 18FDG PET-CT."

Journal • Neuroendocrine Tumor • Oncology • Pancreatic Cancer • Solid Tumor • CA9 • CASP3 • EIF4EBP1 • LDHA • SLC2A1

Changes in Melanoma Cell Morphology Following Inhibition of Cell Invasion by Third-Generation mTOR Kinase Inhibitors. (PubMed, Int J Mol Sci) - "The study used mTOR kinase inhibitors: Everolimus and Torkinib; dual PI3K/mTOR inhibitors BEZ-235 and Omipalisib; and the mTORC1/2 inhibitor OSI-027. These compounds were used both as monotherapy and in combination with the MEK1/2 inhibitor AS-703026...The morphology of cells also changed significantly: their thickness, volume, roughness, convexity of shape, and irregularity, which may be a good diagnostic and prognostic factor for the response to treatment. Our studies to date on the effect of three generations of mTOR kinase inhibitors on the inhibition of the invasion process, the activation of apoptosis, and the reduction in cell proliferation suggest that they may be an important target for anticancer therapy."

Journal • Genetic Disorders • Melanoma • Oncology • Skin Cancer • Solid Tumor • MMP2 • MMP9

EETs Reduction Contributes to Granulosa Cell Senescence and Endometriosis-Associated Infertility via the PI3K/AKT/mTOR Signaling Pathway. (PubMed, Adv Sci (Weinh)) - "14, 15-EET treatment alleviated GC senescence and improved fertility by inhibiting excessive PI3K/AKT/mTOR signaling pathway activation in EM-GCs, with BEZ-235-mediated inhibition of this pathway significantly alleviating ROS-induced cell senescence and abnormal COC expansion. Oxidative stress-induced decreased EZH2/H3K27Me3 histone methylation led to elevated EPHX2 expression patterns in EM-GCs. Decreased 14, 15-EET levels resulted in ROS accumulation, reduced EZH2 enzymatic activity, less EPHX2/H3K27Me3 histone methylation, and increased EPHX2 protein expression levels, which further reduced 14, 15-EET levels in a vicious feedback loop."

Journal • Endometriosis • Gynecology • Infertility • Sexual Disorders • Women's Health

Identification of diabetes-related signatures as prognostic and therapeutic biomarkers in colon cancer. (PubMed, Discov Oncol) - "Diabetes plays an important role in CC pathogenesis, and NVP-BEZ235 may be a promising therapeutic drug for CC patients with diabetes."

Biomarker • Journal • Tumor mutational burden • Colon Cancer • Colorectal Cancer • Diabetes • Metabolic Disorders • Microsatellite Instability • Oncology • Solid Tumor • Type 2 Diabetes Mellitus • MSI • TMB

Combination of Berberine and NVP-BEZ235 inhibits metastasis of triple-negative breast cancer MDA-MB-231 cell line. (PubMed, Biochem Biophys Res Commun) - "Ligand tracer results show that the combination of Berberine and NVP-BEZ235 reflects the stabilizing effect of NVP-BEZ235 on Berberine binding kinetics in MDA-MB-231 cells. These findings suggest a synergistic effect of NVP-BEZ235 and Berberine combination inhibiting metastasis of MDA-MB-231 cell line, demonstrating a potential therapy for TNBC."

Journal • Preclinical • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CDH1 • CDH2 • SNAI2

Dual PI3K/mTOR inhibitor NVP-BEZ235 induces cell cycle arrest via autophagy mediated protein degradation of RPL19 in nephroblastoma cell. (PubMed, Front Pharmacol) - "The in vivo results further suggest that the suppression of RPL19 enhances the therapeutic effects of NVP-BEZ235. These findings highlight the potential of NVP-BEZ235 as a promising therapeutic strategy for nephroblastoma, potentially through modulation of autophagy and RPL19 expression."

Journal • Kidney Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • Targeted Protein Degradation • Wilms Tumor

Heterogeneous Activation of Signaling Pathways and Therapeutic Vulnerabilities in KSHV-Associated Primary Effusion Lymphoma Cell Lines. (PubMed, J Med Virol) - "Importantly, dual PI3K/mTOR inhibitors BGT226 and Dactolisib demonstrated superior efficacy by potently inhibiting proliferation and inducing apoptosis and cell cycle arrest in all PEL cell lines, suggesting an advantage in overcoming compensatory feedback mechanisms. These findings underscore the heterogeneity of PEL and the need for personalized therapeutic strategies. Our results support the potential of combinatorial or multi-targeted approaches to improve treatment outcomes for PEL patients and warrant further preclinical and clinical investigations."

Heterogeneity • Journal • Preclinical • Hematological Malignancies • Kaposi Sarcoma • Lymphoma • Oncology • Sarcoma • Solid Tumor

NVP-BEZ235 enhances autophagy and ameliorates cognitive deficits by targeting tauopathies. (PubMed, Exp Mol Pathol) - "Collectively, these findings demonstrate that NVP-BEZ235 facilitates tau clearance by enhancing autophagy through mTOR inhibition, thereby mitigating cognitive deficits and neuroinflammation in tauopathy models. This study supports the therapeutic potential of NVP-BEZ235 as a promising candidate for the treatment of tau-related neurodegenerative diseases."

Journal • CNS Disorders • Cognitive Disorders • Hematological Disorders • Hematological Malignancies • Lymphoma • Oncology • Solid Tumor • IL1B • IL6 • TNFA

BCL-2 family inhibition enhances MTORC1/2 inhibition in PIK3CA mutant colorectal cancer. (PubMed, Mol Cancer Ther) - "Across multiple in vitro and in vivo CRC models, navitoclax enhanced PI3K/MTOR inhibition (copanlisib, sapanisertib, and dactolisib) and induced apoptosis. Furthermore, we identify BCL-xL as the major BCL-2 family target important for the response to this combination in this setting. This provides a strong rationale for MTORC1/2 and BCL-2 family inhibition as a potential treatment strategy for PIK3CA mutant CRCs."

IO biomarker • Journal • Colorectal Cancer • Oncology • Solid Tumor • BCL2 • BCL2L1 • KRAS • PIK3CA

Bim and Mcl-1 Coordinate NVP-BEZ235-induced Renal Cell Carcinoma Cell Apoptosis. (PubMed, Arch Biochem Biophys) - "Bcl-2 inhibitor ABT-737 and Mcl-1 inhibitor AZD5991 predisposed NVP-BEZ235-treated cells to transform into the apoptotic phenotype. PI3K inhibitor LY294002 and Stat3 inhibitor AG490 duplicated the sensitized actions towards NVP-BEZ235...Data of in vivo tumor-bearing studies further revealed a better anti-tumor potential in the combination treatment of NVP-BEZ235 and MEK/ERK inhibitors without obvious toxicity. Our findings suggest that the feedback activation of pro-survival machinery is likely to be the main cause of cancer cells being refractory to NVP-BEZ235, and a combination treatment is a feasible strategy to sensitize cancer cell responses."

IO biomarker • Journal • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • Targeted Protein Degradation • BCL2L11 • MCL1

Epimedium Brevicornu and Curculigo orchioides inhibit osteoclast autophagy by degrading the level of miRNA-199 to regulate the mTOR signaling pathway. (PubMed, J Orthop Surg Res) - "EBCO delays the progression of osteoporosis by reducing miRNA-199 in osteoclasts to regulate mTOR signaling and inhibit autophagy. Further research is needed to explore new avenues of clinical application."

Journal • Osteoporosis • Rheumatology • BECN1

Integration of whole genome sequencing analysis with unique patient-derived models reveals clinically relevant drug targets in TFCP2 fusion-defined rhabdomyosarcoma. (PubMed, Mol Cancer Ther) - "Preclinical assessments revealed that targeting the pathway with a small molecule PI3K/mTOR inhibitor dactolisib presents a promising treatment approach for this rare cancer, decreasing cancer cell viability in vitro and significantly reducing tumor growth in vivo...Strikingly, combined inhibition of PRMT5 and PI3K/mTOR signaling synergistically enhanced anti-tumor response and significantly improved survival in vivo. This study highlights the importance of new patient-derived models for the elucidation of the biology of rare cancers, and identification of new therapeutic entry points, with clear implications for the future treatment of TFCP2-rearranged IORMS."

Journal • Oncology • Rhabdomyosarcoma • Sarcoma • Solid Tumor • CDKN2A • MTAP • TFCP2