dactolisib (RTB101) / Adicet Bio - LARVOL DELTA

Mechanistic study of PI3K/mTOR signaling pathway combined with immune checkpoint blockade on immune balance in hepatocellular carcinoma and heart transplantation (TTS 2026) - "This, in turn, limits inflammatory cytokine production. Furthermore, we propose that NVP-BEZ235 enhances cardiomyocyte autophagy as a compensatory mechanism to sustain graft survival.Graphical abstract"

Checkpoint block • Checkpoint inhibition • Hepatocellular Cancer • Oncology • Solid Tumor • Transplant Rejection • Transplantation

Methylsulfonylmethane protects against lethal MRSA infection via binding to PIK3CB to increase macrophage phagocytic function and nitric oxide production. (PubMed, Life Sci) - "MSM alleviates lethal MRSA infection by enhancing macrophage phagocytosis and promoting NO production to eliminate intracellular bacteria. These findings position MSM as a promising therapeutic agent against drug-resistant bacterial infections, offering a novel strategy for managing sepsis."

Journal • Infectious Disease • Septic Shock • ITGAM • LAMP1 • PIK3CB

Integrative analysis of methylation-driven genes and macrophage subtypes defines prognostic biomarkers in clear-cell renal cell carcinoma. (PubMed, Comput Methods Biomech Biomed Engin) - "Molecular docking identified Dactolisib as a potential therapeutic agent. These findings provide novel biomarkers and potential therapeutic targets for prognosis and personalized treatment of ccRCC."

Biomarker • Journal • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Solid Tumor • HLA-DRA • RNASE2

Interrogating PI3K to induce PD-L1 expression in oral carcinoma. (ASCO 2018) - "Correlative studies with PI3K inhibitor pictilisib and dual PI3K & mTOR inhibitor dactolisib were performed. Using small molecule modulators of PI3K signaling, we demonstrate that the PI3K pathway can play opposing roles in the induction of PD-L1 and MHC I by IFN-g in oral squamous carcinoma cells. Further studies in other epithelial cancers and clinical correlates are warranted."

IO biomarker • PD(L)-1 Biomarker • Oral Cancer

CD36 AS A POTENTIAL MARKER AND THERAPEUTIC TARGET OF LEUKEMIC STEM CELLS IN ACUTE MYELOID LEUKEMIA (EHA 2026) - "We also found that the PI3 kinase blocker BEZ235 and the BRD4-targeting drugs JQ1 and dBET6 counteract CD36 expression in AML cells, indicating that CD36 is regulated by oncogenic signaling pathways. The CD36-related fatty acid uptake blocker SSO reduced cell growth/survival in U937 cells and primary AML cells including LSC, and suppressed engraftment of U937 cells in NSGS mice. Whether CD36 can be developed far enough to reach clinical application in AML, remains to be determined."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • ANXA5 • BRD4 • CD34 • CD36 • PTPRC • SCARB1

Establishment and validation of a prognostic model for pancreatic cancer utilizing genes of tumor-associated neutrophils. (PubMed, Discov Oncol) - "New TANs-related biomarkers have been found that effectively forecast the prognosis of patients suffering from PAAD."

Journal • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • IL18BP • PSCA

Identification and external validation of a prognostic signature based on bone morphogenetic protein-related mRNAs for kidney renal clear cell carcinoma. (PubMed, Discov Oncol) - "This nine-BRM prognostic model serves as a potential prognostic stratification tool that may complement existing clinical parameters in evaluating the outcomes of KIRC patients."

Journal • Tumor mutational burden • Clear Cell Carcinoma • Clear Cell Renal Cell Carcinoma • Oncology • Renal Cell Carcinoma • Solid Tumor • CA8 • ITGAX • L1CAM • TMB • TUBB2B

WDR72 Drives Esophageal Squamous Cell Carcinoma Progression by Inhibiting Autophagy via the PI3K/Akt/mTOR Pathway. (PubMed, Kaohsiung J Med Sci) - "Notably, the PI3K/mTOR inhibitor BEZ235 abolished the pro-malignant effects and reversed the autophagy suppression induced by WDR72 overexpression. Collectively, our findings establish that WDR72 acts as an oncogene in ESCC by promoting proliferation, survival, and metastasis via activating the PI3K/Akt/mTOR signaling to suppress autophagy."

Journal • Esophageal Cancer • Esophageal Squamous Cell Carcinoma • Oncology • Squamous Cell Carcinoma • BECN1 • WDR72

High-throughput phenotypic profiling of patient-derived colon cancer organoids to reveal a chemoresistant, AKT-driven tumor subpopulation and treatment strategy. (ASCO 2026) - "Diverse CRC PDOs representing multiple Consensus Molecular Subtypes were treated with a combination of 5-Fluorouracil and Oxaliplatin (FOX), imaged utilizing a biomarker panel identified using transcriptomic data, and analyzed using our newly developed phenotypic profiling pipeline...Targeting this survival phenotype, we also demonstrate that transient pre-treatment with the clinically utilized PI3K/mTOR dual inhibitor Dactolisib effectively sensitizes CRC PDOs to FOX, synergizing with this standard-of-care chemotherapy regimen and reducing the fraction of chemoresistant cells... Our findings highlight the power of personalized organoid-based phenotypic profiling for dissecting molecular mechanisms of therapeutic resistance and support the rationale for transient PI3K/mTOR inhibition as a strategy to improve CRC treatments and outcomes."

Clinical • Colon Cancer • Colorectal Cancer • Oncology • Solid Tumor

Integrated analysis of programmed cell death-related genes identifies CORO1A as an apoptosis-associated gene in acute myeloid leukemia. (PubMed, PeerJ) - "OncoPredict suggested higher sensitivity in the high-risk group to 5-fluorouracil, PI3K-AKT-mTOR inhibitors (afuresertib, pictilisib, taselisib, dactolisib), and the MET inhibitor savolitinib. Multi-omic integration of PCD-related genes delineates PCD-driven heterogeneity in AML and yields a robust five-gene prognostic model with therapeutic implications. CORO1A emerges as a potential apoptosis-associated oncogene that promoting AML cell survival."

IO biomarker • Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • ANXA5 • BCL2 • CD31 • CORO • CXCR3 • IL10 • ITGA4 • PECAM1 • PPBP

Construction of a prognostic prediction model for diffuse large B-cell lymphoma patients based on ferroptosis-related LncRNAs. (PubMed, Discov Oncol) - "The prognostic model constructed based on ferroptosis-related lncRNAs demonstrates considerable reliability. It not only effectively predicts patient survival but also reflects tumor immune status and drug response characteristics, showing potential as an auxiliary tool for prognosis assessment and personalized treatment in DLBCL."

Journal • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Targeted Protein Degradation • CD8

BEZ235 inhibits Cryptosporidium parvum infection in mice by targeting the PI3K-NF-κB-c-MYB/BCL2A1 axis to restore host cell apoptosis. (PubMed, Microb Pathog) - "In a murine model of C. parvum infection, oral BEZ235 (15 mg/kg/day) exhibited superior therapeutic efficacy to paromomycin (50 mg/kg/day), reducing fecal oocyst shedding by 61.4% (vs. 42.9% with paromomycin), ileal parasite burden by 60.3% (vs. 42.8% with paromomycin), and markedly alleviating intestinal epithelial damage. These findings deepen our understanding of the intracellular survival strategy of C. parvum and highlight BEZ235 as a promising candidate for cryptosporidiosis treatment."

Journal • Preclinical • Infectious Disease • BCL2A1 • CASP3 • CASP9

Novel therapeutic strategies targeting MECOM rearranged AMLs discovered by unbiased drug screen (AACR 2025) - "Co-targeting with BETi and other identified sensitivities such as the IAP family inhibitor (LCL161) or Bcl-xL inhibitor (navitoclax or A1155463) also exhibited synergistic lethality in 3q26.2-r AML cell lines and PD AML cells. 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."

Acute Myelogenous Leukemia • Oncology • BCL2L1 • GATA2 • MECOM • MYC • PIK3CA • TNFA • XIAP

Unraveling SMARCA1's role in cancer progression, drug resistance, and muscle differentiation through EMT-related signaling, TGF-β pathway, and key transcription factors SNAI1 and EGR1 (AACR 2025) - "Further cell survival assays revealed that SMARCA1 KO cells are particularly sensitive to the HDAC2 inhibitor Mocetinostat and the MEK inhibitor Trametinib, proposing that targeting SMARCA1 in combination with HDAC2 or MEK inhibition could be an effective therapeutic approach for RMS...Additionally, SMARCA1 KO cells responded differently to both canonical and non-canonical TGF-β pathway inhibitors, including SB505124 (TGFBR1 inhibitor), the PI3K-mTOR inhibitor Dactolisib, and Withaferin A (NF-κB inhibitor). Notably, these TGF-β pathway inhibitors effectively overcame resistance in ARMS cells with SMARCA1 expression, exposing specific vulnerabilities in these otherwise resistant cells. Together, our findings suggest that targeting both canonical and non-canonical TGF-β pathways, alongside SMARCA1, presents promising therapeutic strategies for overcoming drug resistance and potentially limiting RMS progression."

Oncology • Rhabdomyosarcoma • Sarcoma • Solid Tumor • CDK4 • EGR1 • HDAC2 • MYCN • Myogenin • NFKB2 • PPP2R5C • PTEN • SMARCA4 • SMARCD3 • SNAI1 • TGFB1 • TGFBR1

Identifying novel therapies from unbiased screens in AML with MECOM re-arrangement (AACR 2024) - "Consistent with this, co-treatment of mivebresib with SMAC mimetic birinapant or IAP inhibitor LCL161 was synergistically lethal against 3q26.2-r cells. 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."

Acute Myelogenous Leukemia • Oncology • BCL2L1 • BRD4 • CASP3 • CDK4 • HEXIM1 • MCL1 • MECOM • mTOR • MYC • PIK3CA • XIAP

BEZ235 enhances the photodynamic antitumor efficacy of hypoxia-responsive BODIPY prodrug nanoparticles by inhibiting the PI3K/mTOR pathway and alleviating hypoxia. (PubMed, Colloids Surf B Biointerfaces) - "The hypoxic -responsive photodynamic properties of BNP, combined with BEZ's oxygen consumption-inhibiting capacity, can enhance tumor suppression rates. This strategy of nanomedicine development by capitalizing on the synergistic effect between active ingredients will avoid the low efficacy and adverse effects of monotherapies."

Journal • Oncology • Solid Tumor

AUM-302, a novel triple PIM/PI3K/mTOR inhibitor, synergizes with RAS inhibition and impedes the growth of pancreatic ductal adenocarcinoma spheroids and organoids. (PubMed, Front Pharmacol) - "Single- and dual-kinase inhibitors TP-3654, GDC-0941, BEZ-235, respectively, and DMSO were used as controls. The synergy studies were performed using AUM-302 and the RAS inhibitor RMC-6236...By blocking kinase activity, AUM-302 demonstrates potent inhibition in PDAC cell lines and organoids across two 3D culture formats. Treatment with this novel triple PIM/PI3K/mTOR inhibitor may also chemosensitize PDAC to other cancer therapies, such as RAS inhibitors."

Journal • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor

PFOS exposure at environmentally relevant concentrations promote papillary thyroid carcinoma progression through PI3K/AKT/mTOR-mediated epithelial-mesenchymal transition. (PubMed, Environ Res) - "These pro-tumor effects were partially reversed by pharmacological inhibitor BEZ235 for PI3K/mTOR. In vivo validation using a mouse xenograft model confirmed that PFOS exposure promotes tumor growth and upregulates the same pathway and effector molecules. This study provides integrated clinical and experimental evidence that PFOS exposure at environmentally relevant concentrations promotes PTC progression by inducing PI3K/AKT/mTOR-mediated EMT and associated enzyme secretion, providing crucial experimental evidence for the toxic role of PFOS as an environmental contaminant in thyroid tumors and underscoring the urgent need for enhanced environmental health risk assessment and regulation."

Journal • Endocrine Disorders • Oncology • Solid Tumor • Thyroid Gland Carcinoma • Thyroid Gland Papillary Carcinoma • CTNNB1 • MMP2 • MMP9 • SNAI1

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