vistusertib (AZD2014) / AstraZeneca - LARVOL DELTA

Single-Cell Lineage Tracing Uncovers Resistance Signatures and Sensitizing Strategies to FLT3 Inhibitors in Acute Myeloid Leukemia. (PubMed, Cancer Res) - "Here, we applied our recently developed single-cell lineage tracing method ReSisTrace to identify cells that are intrinsically resistant or sensitive to the FLT3 inhibitors midostaurin and quizartinib in AML with FLT3-ITD mutations...In addition, in an FLT3-ITD-positive AML patient-derived xenograft (PDX) mouse model, the CC-90009 and quizartinib combination showed significantly higher anti-tumor efficacy and prolonged overall survival compared to either treatment alone...Vistusertib (mTOR inhibitor), linsitinib (IGF1R and insulin receptor inhibitor), and meisoindigo (IGF1R and Src family kinase inhibitor), all inhibiting pathways parallel to or downstream of oncogenic FLT3 signaling, were predicted and validated to sensitize FLT3-mutated cell lines and primary cells to FLT3 inhibitors. Collectively, these findings demonstrate the ability of ReSisTrace to unveil pre-existing transcriptional features of treatment vulnerability in hematological cancers and elucidate..."

Journal • Preclinical • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • FLT3 • GSPT1 • IR

AZD2014 and Fulvestrant in Patients With ER+ Advanced Metastatic Breast Cancer (clinicaltrials.gov) - P1 | N=99 | Active, not recruiting | Sponsor: AstraZeneca | Trial completion date: Sep 2028 ➔ Feb 2026

Trial completion date • Breast Cancer • Estrogen Receptor Positive Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor

Interplay between Inflammatory Microenvironment and RUNX1-Mediated Transcriptomic Changes Drives Defective Hematopoiesis in Familial Platelet Disorder (ASH 2023) - "Interestingly, inhibition of mTORi (rapamycin and AZD2014), PI3Ki (idelalisib), and JAKi (ruxolitinib) showed an increase in percentage of megakaryocytes (up to 2-fold, p<0.05) and a decrease in monocytes (up to 0.6-fold change, p<0.05). FPD HSPCs manifest defective megakaryopoiesis with increased myelopoiesis. The elevated autocrine and paracrine inflammatory stress is an early event in FPD, driving myeloid differentiation. This inflammatory stress mediates activation of PI3K/mTOR and JAK signaling, leading to augmented myeloid differentiation."

Atopic Dermatitis • Dermatology • Hematological Disorders • Hematological Malignancies • Immunology • Leukemia • Oncology • Thrombocytopenia • CCL2 • CXCL8 • IL1B • RUNX1 • TNFA

The mTORC1/2 dual inhibitor AZD2014 enhances inotuzumab ozogamicin-induced apoptosis in B-cell non-Hodgkin lymphoma cells via lysosomal function activation (SITC 2025) - "We previously demonstrated that mTORC1/2 inhibition restores lysosomal function and sensitizes acute myeloid leukemia cells to gemtuzumab ozogamicin.1 2 Based on these findings, in this study we investigate whether the combination of IO with an mTORC1/2 inhibitor can enhance antitumor efficacy in B-cell NHL by restoring lysosomal activity.Methods We evaluated the combination of IO and the mTORC1/2 inhibitor AZD2014 in seven B-cell NHL cell lines (KML-1, Daudi, TK, SLVL, Ramos, Raji, RL). However, resistance mediated by Bcl-2 and MDR-1 remains a barrier. Strategies to overcome these resistance mechanisms are needed to optimize ADC-based therapies for B-cell NHL.Ethics Approval The project received approval from the ethics committees of Kobe University (#1481).Abstract 689 Figure 1Request permissionsThe cytotoxic effect of inotuzumab ozogamicin (IO) was enhanced by the combination of the mTORC1/2 inhibitor AZD2014 in B-cell non-Hodgkin lymphoma (B-cell NHL) cell..."

IO biomarker • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • B Acute Lymphoblastic Leukemia • B Cell Lymphoma • B Cell Non-Hodgkin Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • ABCB1 • ANXA5 • BCL2 • CD22

Overcoming of acquired Everolimus resistance in cell line models of well-differentiated pancreatic neuroendocrine tumors (DGHO 2025) - "We determined the dose-response curves in drug-selected clones compared to vehicle treated control cells for the rapalogs EVE and rapamycin, the alkylating chemotherapeutic agents 5-Fluorouracil (5‑FU) and Streptozotocin, as well as ATP-competitive mTOR inhibitors OSI‑027 and AZD2014...However, EVE-resistant clones were still as susceptible to treatment with second generation mTOR-inhibitors OSI-027 or AZD2014 as control cells... This work indicates a potential common underlying process, by which the cell line clones increase their resistance to mTORC1 inhibition in vitro. Treatment with ATP-competitive mTOR inhibitors, which block both, mTORC1 and 2, were able overcome the acquired resistance in EVE-selected cell clones. In summary, the EVE-resistant cell lines generated in this work may function as preclinical models to further investigate potential strategies to overcome acquired EVE-resistance to improve personalized treatment options."

Preclinical • Neuroendocrine Tumor • Oncology • Pancreatic Cancer • Solid Tumor

A novel gene therapy combination targeting non-small cell lung cancer (EACR 2025) - "AZD2014 (vistusertib), a dual mTOR inhibitor, targets both mTORC1 and mTORC2 complexes within this pathway... These results elucidate the validity and effectiveness of this tripartite combination which is currently being further studied in both 2D and 3D models to effectively target NSCLC and to establish safety profiles of this novel NSCLC treatment."

Gene therapy • Gene Therapies • Large Cell Carcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • EIF4E • HSPB1

A comprehensive systematic review of prognostic factors, survival outcomes, and the role of targeted therapies in endometrial cancer. (PubMed, Ir J Med Sci) - "In conclusion, anastrozole and vistusertib emerge as effective targeted therapies for endometrial cancer, supported by clinical trial evidence demonstrating reduced PFS and improved protein detection. Additionally, the carboplatin-paclitaxel combination and radiotherapy in monotherapy show promising clinical outcomes. These findings contribute to a comprehensive understanding of prognostic factors, targeted therapies, and survival outcomes in endometrial cancer, emphasizing the need for further research and clinical trials for optimal disease management."

Biomarker • Journal • Review • Endometrial Cancer • Oncology • Solid Tumor

The role of the tumour microenvironment in lung cancer and its therapeutic implications. (PubMed, Med Oncol) - "Promising results have been observed with mTOR inhibitors like CC-115 and Vistusertib, especially when combined with immune checkpoint inhibitors, and with JAK inhibitors such as Ruxolitinib, AZD4205, and Filgotinib. These strategies represent a promising direction for lung cancer therapy. This review explores the intricate relationship between the TME and lung cancer, focussing on novel therapeutic approaches that target immune cells, signalling molecules, and fibroblasts within the TME to improve patient outcomes."

Journal • Review • Lung Cancer • Oncology • Solid Tumor

Drug sensitivity patterns across FAB subtypes and molecular mutations in AML. (ASCO 2025) - "M1 samples (n=22 patients) demonstrated higher sensitivity to Navitoclax (σsDSS = 15.89), while combinations with mTOR inhibitors like Navitoclax + PF-04691502 (σsDSS = 13.97) and Navitoclax + Vistusertib (σsDSS = 13.72) showed promise...M4 subtypes (n=2 patients) were most sensitive to BAY 87-2243 (σsDSS = 15.98), with dual combinations like BAY 87-2243 + Cerdulatinib (σsDSS = 14.21) and BAY 87-2243 + Pevonedistat (σsDSS = 14.13) maintaining strong responses...In M4 eos (n=9 patients), Pimasertib demonstrated notable effectiveness (σsDSS = 14.43), with dual-agent combination such as Pimasertib + SCH772984 (σsDSS = 14.24) supporting RAS/ERK pathway inhibition. Despite rare M4/M5 subtypes (n=2 patients) showing limited Refametinib sensitivity (σsDSS = 8.75), their minimal sample size precludes definitive conclusions...Likewise, mutation analysis revealed that NPM1-mutated samples showed increased sensitivity to Venetoclax (σsDSS = 13.28) and PF-04691502 (σsDSS =..."

Acute Myelogenous Leukemia • FLT3 • NPM1

National Lung Matrix Trial: Multi-drug Phase II Trial in Non-Small Cell Lung Cancer (clinicaltrials.gov) - P2 | N=423 | Active, not recruiting | Sponsor: University of Birmingham | Trial completion date: Sep 2024 ➔ Sep 2025 | Trial primary completion date: Sep 2024 ➔ Sep 2025

IO biomarker • Trial completion date • Trial primary completion date • Lung Cancer • Lung Non-Small Cell Squamous Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • NKX2-1 • TP63

mTORC1/2 Inhibitor AZD2014 or the Oral AKT Inhibitor AZD5363 for Recurrent Endometrial and Ovarian (clinicaltrials.gov) - P1 | N=159 | Active, not recruiting | Sponsor: M.D. Anderson Cancer Center | Phase classification: P1/2 ➔ P1

Phase classification • Breast Cancer • Endometrial Adenocarcinoma • Endometrial Cancer • Fallopian Tube Cancer • HER2 Breast Cancer • High Grade Serous Ovarian Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Negative Breast Cancer • Oncology • Ovarian Cancer • Peritoneal Cancer • Solid Tumor • Triple Negative Breast Cancer • Uterine Cancer • BRCA • ER • MUC16 • PGR

Synthesis and Biological Evaluation of MEK/mTOR Multifunctional Inhibitors as Novel Anticancer Agents. (PubMed, J Med Chem) - "The mitogen-activated protein kinase (MAPK) and mechanistic target of rapamycin (mTOR) signaling nodes play a crucial role in many human cancers...A series of mTOR inhibitor analogs of AZD8055 and AZD2014 were designed to allow for covalent linking to a potent MAPK kinase (MEK) inhibitor to produce a single, bivalent chemical entity...Additionally, compound LP-65 demonstrated significant modulation of MEK and mTOR signaling activity in human glioma cells (D54) and human melanoma cells (A375), with a corresponding decrease in cellular proliferation and migration. Treatment of mice with LP-65 (40 mg/kg) having a myeloproliferative neoplasm, myelofibrosis, revealed down modulation of in vivo signaling pathways and therapeutic efficacy."

Journal • Brain Cancer • Glioma • Melanoma • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • Solid Tumor

Potential novel interventions of oncohistones, epigenetic modifications, and RNA processing machinery in betel-nuts related HNSCC in Taiwan (AACR 2025) - "PI3K/AKT/mTOR interventions, ALK/IGF1R inhibitor, CDK4/6 inhibitor, BCl2 inhibitor, WEE1 inhibitor, ATR inhibitor, DNA-PK inhibitor, AT2AR inhibitor, Mcl-1 inhibitor, MEK1/2 inhibitor, JAK2 inhibitor, CXCR4 inhibitor, FAK inhibitor, p53 reactivator, MDM2 inhibitor, SHP2 inhibitor, PARP7 inhibitor, IAP inhibitor, GLS1 inhibitor, eribulin, & VEGFR2/ PDGFR/FGFR or VEGFR2/c-MET/Axl triple blockage might be effective on TW2.6 and reverse treatment refractoriness, through the inhibition of mesenchymal transformation, pRB, & PI3K/AKT /mTOR signaling and modulation of stemness & PD1/PDL1 pathway...Disrupting NSD1 in HNSCC cell lines led to CpG hypomethylation & enhanced cisplatin sensitivity. TW2.6 used to test (1)in vitro drug sensitivity to (a)Chemical Modulators of Splicing; (b)PRMT5 inhibitor; (c)CDK9 inhibitor, EZH2i, DNMT3i, BRD/BET4i, and HDACi; (d)NSD1/SETD2 inhibitor; (e)METTL3 inhibitor; (2)synergistic effects with other therapies by MTT assay, colony..."

IO biomarker • Head and Neck Cancer • Oncology • Squamous Cell Carcinoma of Head and Neck • AKT1 • ALK • ARID1B • ATM • AXL • BRD4 • CCND3 • CDK12 • CXCR4 • DDR2 • EPHB1 • FAT1 • FGF10 • FGFR • FLCN • HRAS • KDM5A • KDR • METTL3 • MITF • NSD1 • PDGFRB • PIK3CA • RICTOR • RPS6KB1 • SDHA • SETD2 • SOX9 • STK11 • TERT • TIPARP • TMB • TNFAIP3

HUDSON: Phase II Umbrella Study of Novel Anti-cancer Agents in Patients With NSCLC Who Progressed on an Anti-PD-1/PD-L1 Containing Therapy (clinicaltrials.gov) - P2 | N=527 | Active, not recruiting | Sponsor: AstraZeneca | Trial primary completion date: Sep 2026 ➔ Sep 2024

Biomarker • IO biomarker • Trial primary completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

BISCAY: Open-Label, Randomised, Multi-Drug, Biomarker-Directed, Phase 1b Study in Pts w/ Muscle Invasive Bladder Cancer (clinicaltrials.gov) - P1 | N=117 | Active, not recruiting | Sponsor: AstraZeneca | Trial completion date: Mar 2025 ➔ Jan 2026

Biomarker • Trial completion date • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • CCNE1 • CDKN2A • HRD • MYCL • MYCN • RB1

A phase II trial of mTORC1/2 inhibition in STK11 deficient non small cell lung cancer. (PubMed, NPJ Precis Oncol) - P2 | "In arm B2 of the National Lung Matrix Trial 54 patients with NSCLC received vistusertib, of which 49 were STK11-deficient (30 with KRAS mutation (B2D), 19 without (B2S))...In vitro studies show adaptive resistance to mTORC1/2 inhibition via AKT reactivation. (NCT02664935, ISRCTN38344105, EudraCT 2014-000814-73, 10 June 2015)."

Journal • P2 data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS • SLC2A1 • SMARCA4 • STK11

A phase 1 study of the combination of BH3-mimetic, navitoclax, and mTORC1/2 inhibitor, vistusertib, in patients with advanced solid tumors. (PubMed, Cancer Chemother Pharmacol) - P1/2 | "A tolerable dose of navitoclax at 150 mg orally daily plus vistusertib at 35 mg orally twice daily was identified in patients with advanced solid tumors and established as the recommended phase 2 dose (RP2D). Further efficacy assessment of this combination, in a planned phase 2 expansion in patients with relapsed small cell lung cancer, was terminated due to discontinuation of vistusertib."

Journal • P1 data • Hematological Disorders • Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • Thrombocytopenia • BCL2

Use of metabolic imaging to monitor heterogeneity of tumour response following therapeutic mTORC1/2 pathway inhibition. (PubMed, Dis Model Mech) - "An integrated multi-modal imaging workflow was developed to assess the heterogeneity of AZD2014 (mTORC1/2 inhibitor) response in a PTEN-null renal cancer model...Increasing PI3K-AKT inhibition by combining with AZD8186 (PI3Kβ inhibitor) further decreased the control-like metabolic signature, showing PI3K-dependent resistance. This demonstrates that MSI-based workflows yield novel insights into the pharmacodynamic effects of mTORC1/2 inhibition in tumours, which classical biomarkers do not resolve. Coupling these workflows with spatial-omics approaches can deliver greater insights into heterogeneity of treatment response."

Heterogeneity • Journal • Kidney Cancer • Oncology • Solid Tumor • PIK3CB • PTEN • SLC2A1

A novel acquired resistance mechanism to 5-aminolevulinic acid-mediated photodynamic therapy with ABCG2 inhibition. (PubMed, Photochem Photobiol) - "ALA-PDT in combination with either an ABCG2 tool inhibitor Ko143 or a repurposed clinically-relevant ABCG2 inhibitor lapatinib was highly effective in eradicating the H4 human glioma cells, resulting in minimal cell survival after treatment...They also exhibited similar responses to PpIX-PDT and mTOR inhibitor AZD2014, suggesting that alterations in PDT sensitivity and mTOR pathway had little contribution to the development of resistance phenotype. By determining the intracellular and extracellular PpIX levels, the activities and protein levels of heme biosynthesis enzymes, we found that porphobilinogen deaminase (PBGD) activity and protein level were significantly reduced in the resistant sublines, causing resistance to PDT by substantially reducing PpIX biosynthesis. A novel acquired resistance mechanism to ALA-PDT with ABCG2 inhibition has been uncovered."

Journal • Preclinical • Brain Cancer • CNS Tumor • Glioma • Oncology • Solid Tumor • ABCG2

SAFIR02_Breast - Efficacy of Genome Analysis as a Therapeutic Decision Tool for Patients With Metastatic Breast Cancer (clinicaltrials.gov) - P2 | N=1460 | Active, not recruiting | Sponsor: UNICANCER | Trial completion date: Dec 2024 ➔ Dec 2025

IO biomarker • Trial completion date • Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor

ESMART: European Proof-of-Concept Therapeutic Stratification Trial of Molecular Anomalies in Relapsed or Refractory Tumors (clinicaltrials.gov) - P1/2 | N=455 | Recruiting | Sponsor: Gustave Roussy, Cancer Campus, Grand Paris | Trial completion date: Aug 2027 ➔ Feb 2031 | Trial primary completion date: Aug 2027 ➔ Feb 2031

Trial completion date • Trial primary completion date • Hematological Malignancies • Oncology • Pediatrics

HUDSON: Phase II Umbrella Study of Novel Anti-cancer Agents in Patients With NSCLC Who Progressed on an Anti-PD-1/PD-L1 Containing Therapy (clinicaltrials.gov) - P2 | N=531 | Active, not recruiting | Sponsor: AstraZeneca | Trial completion date: Sep 2024 ➔ Sep 2026 | Trial primary completion date: Sep 2024 ➔ Sep 2026

Biomarker • IO biomarker • Trial completion date • Trial primary completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

BISCAY: Open-Label, Randomised, Multi-Drug, Biomarker-Directed, Phase 1b Study in Pts w/ Muscle Invasive Bladder Cancer (clinicaltrials.gov) - P1 | N=117 | Active, not recruiting | Sponsor: AstraZeneca | Trial completion date: Jun 2024 ➔ Mar 2025

Biomarker • Trial completion date • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • CCNE1 • CD8 • CDKN2A • FGFR • HRD • IFNG • IL10 • IL2 • IL6 • MYCL • MYCN • RB1

MANTA: A Randomized Study of AZD2014 in Combination With Fulvestrant in Metastatic or Advanced Breast Cancer (clinicaltrials.gov) - P2 | N=333 | Completed | Sponsor: Queen Mary University of London | Unknown status ➔ Completed

Combination therapy • Metastases • Trial completion • Breast Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2

Increased mTOR activity and RICTOR copy number in small cell lung carcinoma progression. (PubMed, Eur J Cell Biol) - "Additionally, in vitro sensitivity to cisplatin and mTOR inhibitors was evaluated in SCLC cell lines harbouring RICTOR amplification and other mTOR pathway mutations...The importance of these alterations was confirmed both by the sensitising effect of vistusertib in vitro and the RICTOR copy number/expression changes in xenografts. Our study highlights the role of mTORC2 in SCLC progression. Early detection of RICTOR amplification in primary tumours and targeting mTORC2 in these cases may represent a promising novel strategy to develop personalised therapy for metastasis prevention."

Journal • Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • PI3K • RICTOR