danusertib (PHA-739358) / Nerviano Medical Sciences - LARVOL DELTA

Boron Phenylalanine-Modified Polydopamine Nanoparticles for Targeted Delivery of Danusertib in Non-Small Cell Lung Cancer. (PubMed, Int J Nanomedicine) - "In the mouse lung carcinoma in situ model, B-PDA@Danu effectively targeted and accumulated at the site of carcinogenesis, leading to tumor shrinkage. B-PDA@Danu provides a novel nanomedicine approach for anti-NSCLC therapy that enables targeted tumor elimination with low potential toxicity."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Drug-induced senescence by aurora kinase inhibitors attenuates innate immune response of macrophages on gastric cancer organoids. (PubMed, Cancer Lett) - "It was found that DGCs showed drug-induced senescent phenotype after treatment by aurora kinases inhibitors (AURKi) Barasertib-HQPA and Danusertib. The up-regulation of local MCP-1/CCL2 can interact with MCP-1/CCL2 receptor (CCR2) expressed on macrophages and suppress their innate immunity to cancer cells. Overall, the special response of DGC to AURKi suggests that clinicians should select a sequential therapy with senescent cell clearance after AURKi treatment for DGC."

Journal • Gastric Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • CCL2 • CCR2

Aurora Kinases as Novel Targets for the Treatment of Aggressive Meningiomas (EACR 2024) - "Therefore, we investigated the efficacy of AURKAi alisertib, AURKBi barasertib, and the pan-Aurora kinase inhibitor danusertib as potential therapeutics for the treatment of MGMs.Material and Methods RNAi-mediated knockdown experiments were conducted in benign (Ben-Men-1) and anaplastic MGM cell lines (NCH93). Alisertib demonstrated substantial in vivo anti-tumor effects while showing a high tolerability. These novel data suggest that targeting Aurora kinases could offer new therapeutic options for patients with aggressive MGMs in future years."

Brain Cancer • CNS Tumor • Meningioma • Oncology • Solid Tumor • AURKA • AURKB

Understanding the Differences of Danusertib's Residence Time in Aurora Kinases A/B: Dissociation Paths and Key Residues Identified using Conventional and Enhanced Molecular Dynamics Simulations. (PubMed, J Chem Inf Model) - "In addition, the potential dissociation paths of Danusertib in Aurora A and B were characterized, and differences that might be explained by the differential residues in the enzyme's active sites were found. In perspective, it is expected that this computational protocol can be applied to other protein-ligand complexes to understand, at the molecular level, the differences in residence times and amino acids that may contribute to it."

Journal

Suppression of NSCLC progression via the co-administration of Danusertib, an AURK inhibitor, and KRIBB11, an HSF1 inhibitor. (PubMed, Biochem Pharmacol) - "Furthermore, the combination treatment inhibits tumor growth and AKT signaling in the xenograft mouse model, increases levels of the tumor tissue oxidation product malondialdehyde (MDA), and induces DNA damage. To summarize, a potential therapeutic approach for NSCLC may involve dual inhibition of AURK and HSF1, resulting in the downregulation of the PI3K/AKT signaling pathway, and the activation of ROS-mediated mitochondrial and DNA damage pathways."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • BCL2 • CASP3 • CCNB1 • CDK1 • HSF1

The Supression of Migration and Metastasis via Inhibition of Vascular Endothelial Growth Factor in Pancreatic Adenocarcinoma Cells Applied Danusertib. (PubMed, Turk J Gastroenterol) - "Danusertib, a pan-Aurora kinase inhibitor, is predicted to be used as a potential agent in pancreatic cancers due to its antitumor and anti-metastatic effect."

Journal • Cystic Fibrosis • Fibrosis • Gastrointestinal Cancer • Genetic Disorders • Hepatology • Immunology • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Pulmonary Disease • Respiratory Diseases • Solid Tumor

Molecular correlates of drug response to guide therapy in triple-negative breast cancer (SABCS 2023) - "Focusing on a known active drug in TNBC that is approved for patients with metastatic TNBC, we identified multi-omic (protein expression/activity and RNA expression) molecular correlates of response to a chemotherapeutic- SN-38, the payload of Sacituzumab and the active metabolite of irinotecan. Furthermore, combining the pan-AK inhibitor danusertib with berzosertib results in synergistic killing of TNBC cells. As a future direction, we are evaluating this combination in vivo utilizing an ethnically diverse patient-derived xenograft library grown in mice to evaluate this novel combination in a mock clinical trial and to identify molecular correlates of response and resistance that could be used to guide future human trials."

IO biomarker • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • PD-L1

Comprehensive Profiling and Therapeutic Insights into Differentially Expressed Genes in Hepatocellular Carcinoma. (PubMed, Cancers (Basel)) - "Potential therapeutic chemicals are alvocidib, AT-7519, kenpaullone, PHA-793887, JNJ-7706621, danusertibe, doxorubicin and analogues, mitoxantrone, podofilox, teniposide, and amonafide. This multi-omic study offers a comprehensive view of DEGs in HCC, shedding light on potential therapeutic targets and drug repurposing opportunities."

Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Liver Cancer • Oncology • Solid Tumor • AURKA • CCNB1 • CDK1 • RRM2 • TOP2A

Combined inhibition of Aurora Kinases and Bcl-xL induces apoptosis through select BH3-only proteins. (PubMed, J Biol Chem) - "We demonstrate that combination of a BH3-mimetic inhibitor (ABT-737), a selective inhibitor of Bcl-xL, Bcl-2, and Bcl-w, with Alisertib or Danusertib potently induces apoptosis through the Bcl-2 family effector protein Bax. On the other hand, we found Alisertib treatment causes activation of caspase-2, which promotes apoptosis by cleaving Bid into tBid, a suppressor of both Bcl-xL and Mcl-1. Together, these results define the Bcl-2 protein network critically involved in AURK inhibitor-induced apoptosis, and suggest that BH3-mimetics targeting Bcl-xL may help overcome resistance to AURK inhibitors in cancer cells."

Journal • Colon Cancer • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • BCL2 • BCL2L1 • BCL2L2 • MCL1

Widespread genomic/molecular alterations of DNA helicases and their clinical/therapeutic implications across human cancer. (PubMed, Biomed Pharmacother) - "The close association of DHS with the alt-EJ pathway and HRD, and identification of Danusertib as a putative DNA helicase inhibitor have translational significance. Taken together, these findings will contribute to DNA helicase-based cancer therapy."

Journal • Tumor mutational burden • Oncology • BRCA1 • BRCA2 • HRD • TMB

Pan-Aurora Kinase Inhibitor Danusertib Induces Apoptosis of Epstein-Barr Virus-transformed B-Cells Through Caspase and Endoplasmic Reticulum Stress Signaling. (PubMed, Anticancer Res) - "Danusertib treatment led to apoptosis of EBV-transformed B-cells through ER stress-associated proteins and mitochondrial caspase activation. These results suggest that aurora kinases may be valuable targets for potential therapeutic agents against EBV-associated carcinoma."

Journal • Epstein-Barr Virus Infections • Hematological Malignancies • Lymphoma • Oncology • AURKA

Polo-like kinase-1, Aurora kinase A and WEE1 kinase are promising druggable targets in CML cells displaying BCR::ABL1-independent resistance to tyrosine kinase inhibitors. (PubMed, Front Oncol) - "In chronic myeloid leukemia (CML), Aurora kinase A and Polo like kinase 1 (PLK1), two serine-threonine kinases involved in the maintenance of genomic stability by preserving a functional G2/M checkpoint, have been implicated in BCR::ABL1-independent resistance to the tyrosine kinase inhibitor (TKI) imatinib mesylate and in leukemic stem cell (LSC) persistence. Finally, combination of danusertib or volasertib+AZD1775 significantly reduced the clonogenic potential of CD34+ CML progenitors from BC patients. Our results may have implications for the development of innovative therapeutic approaches aimed to improve the outcomes of patients with multi-TKI-resistant or BC CML."

Journal • Chronic Myeloid Leukemia • Hematological Malignancies • Leukemia • Oncology • ABL1 • AURKA • CD34 • PLK1

Aurora kinase B expression shields HNSCC from PI3K inhibition-induced apoptosis through downstream mediators AKT and PDK1 (AACR 2022) - "To use a pharmacologic approach, we combined the pan-Aurora kinase inhibitor danusertib (0-2µM) with PI3K/mTOR inhibitor omipalisib (0-200nM) in 56 HNSCC cell lines for 72h and observed a substantial decrease in cell viability in >80% of NOTCH1WT and >90% of NOTCH1MUT HNSCC lines...Mice bearing NOTCH1MUT xenografts showed complete tumor regression when treated with a combination of pan-PI3K inhibitor Copanlisib and Aurora inhibitor Alisertib as compared to control groups...We identified AURKB as a central player governing the sensitivity to PI3K inhibitor-induced apoptosis in the context of NOTCH1 mutation status in HNSCC through its effects on AKT and PDK1. These novel findings may lead to the development of more robust therapeutic approach for NOTCH1 mutant squamous carcinoma as well as patients who develop acquired resistance to targeted therapies."

Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • AURKA • AURKB • CASP3 • NOTCH1

Combined Inhibition of Polo-Like Kinase-1 and Wee1 as a New Therapeutic Strategy to Induce Apoptotic Cell Death in Neoplastic Mast Cells. (PubMed, Cancers (Basel)) - "Although midostaurin, a multikinase inhibitor active against both wild-type and D816V-mutated KIT, improves organ damage and symptoms, a proportion of patients relapse or have resistant disease. Wee1 inhibition by MK1775 after 24 h treatment with danusertib or volasertib, when cells were arrested in G2 phase and Wee1, was overexpressed and hyper-activated, resulting in a significantly higher rate of apoptosis than that obtained from concomitant treatment with danusertib or volasertib + MK1775 for 48 h. In conclusion, Plk1 and AKA, alone or together with Wee1, are attractive therapeutic targets in neoplastic MCs. Repurposing Plk1 or AKA ± Wee1 inhibitors in advanced clinical development for other indications is a therapeutic strategy worthy of being explored, in order to improve the outcome of patients with advanced SM."

Journal • Oncology • AURKA • CCNB1 • CDK1 • KIT • PLK1 • WEE1

The effect of danusertib, an Aurora kinase inhibitor, onto the cytotoxicity, cell cycle and apoptosis in pancreatic ductal adenocarcinoma cells. (PubMed, J Cancer Res Ther) - "Aurora kinase inhibitor danusertib induced a significant effect of cytotoxic, apoptotic and cell cycle arrest in CFPAC-1 ductal adenocarcinoma cells. Therefore, it may be a potential alternative to the treatment of pancreatic cancers."

Journal • Cystic Fibrosis • Fibrosis • Gastrointestinal Cancer • Genetic Disorders • Hepatology • Immunology • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Pulmonary Disease • Respiratory Diseases • Solid Tumor

Forecasting Gastric Cancer Diagnosis, Prognosis, and Drug Repurposing with Novel Gene Expression Signatures. (PubMed, OMICS) - "Accordingly, we found several repurposed drug candidates, including Trichostatin A, Vorinostat, Parthenolide, Panobinostat, Brefeldin A, Belinostat, and Danusertib. Through text mining analysis and literature search validation, Belinostat and Danusertib were suggested as possible novel drug candidates for GC treatment. These findings collectively inform multiple aspects of GC medical management, including its precision diagnosis, forecasting of possible outcomes, and drug repurposing for innovation in GC medicines in the future."

Journal • Gastric Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • STAT6

Combined inhibition of AURKA and HSF1 suppresses proliferation and promotes apoptosis in hepatocellular carcinoma by activating endoplasmic reticulum stress. (PubMed, Cell Oncol (Dordr)) - "Combined inhibition of AURKA and HSF1 shows an excellent anti-tumor effect on HCC cells in vitro and in vivo, which may be mediated by ERS. These findings suggest that both AURKA and HSF1 may serve as targets for HCC treatment."

Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Immune Modulation • Inflammation • Oncology • Solid Tumor • ATF4 • AURKA

Thyroid hormone plus dual-specificity phosphatase-5 siRNA increases the number of cardiac muscle cells and improves left ventricular contractile function in chronic doxorubicin-injured hearts. (PubMed, Theranostics) - "Genetic lineage tracing using Myh6-MerCreMer::Rosa26fs-Confetti mice and direct cardiomyocyte number counting, along with cell cycle inhibition (danusertib), was used to test if this treatment leads to de novo cardiomyocyte generation and improves LV contractile function. Importantly, a GMP compliant in vivo-jetPEI system for delivery of siRNA is already in use in humans, as is T3. Given these considerations, our findings provide a potentially highly translatable strategy for addressing doxorubicin cardiomyopathy, a currently untreatable condition."

Journal • Cardiomyopathy • Cardiovascular • Congestive Heart Failure • Heart Failure • Oncology

[VIRTUAL] Midostaurin Synergizes with Nilotinib and Dasatinib Restoring SETD2 Expression and Activity in Advanced Systemic Mastocytosis (SOHO 2020) - "siRNA-mediated silencing of AKA and pharmacological inhibition by danusertib rescued SETD2 expression and activity, suggesting that AKA is implicated in SETD2 degradation. AKA overexpression contributes to SETD2 non-genomic loss of function in advSM. KIT and AKA targeting by midostaurin in combination with second-generation tyrosine kinase inhibitors is a promising therapeutic alternative in patients with SETD2/H3K36me3 deficiency. Supported by AIRC project 23001."

Aggressive Systemic Mastocytosis • Oncology • AURKA • KIT

Synthetic lethal therapy to overcome resistance to AURKA inhibition in HPV-negative head and neck cancer (AACR 2018) - "...AURKA is negatively regulated by p53, which causes upregulation of AURKA in the majority of cases of HNSCC, correlating with poor prognosis and cisplatin resistance...This work has identified has several effective combinations, particularly in between alisertib (targeting AURKA), danusertib (AURKA and AURKB), LY2606368/prexasertib (CHK1), and reversine (MPS1)...We will describe in detail mechanistic interactions between specific combinations of value for HNSCC. These drug combinations are likely to represent a new and effective modality for treating TP53-mutated cancers."

Head and Neck Cancer

Pharmacogenomic screen identifies KMT2D mutations as a biomarker of sensitivity to Aurora kinase inhibition in head and neck and cervical squamous cell carcinoma (AACR 2018) - "...Treatment with a dual Aurora A/B inhibitor, danusertib, led to G2M arrest and apoptosis in all 6 tested cell lines...These drugs cause apoptosis and cell cycle arrest in vitro and decrease tumor size in vivo. This is the first published study to demonstrate that mutations in KMT2D (MLL2), which are common in many cancers (16% HNSCC, 12% CESC), correlate with drug sensitivity in 2 independent data sets."

Biomarker • Head and Neck Cancer

IL-6 mediated signaling regulates cytotoxic effect of Burkitt lymphoma cells by combined treatment of Danusertib and BKM120 (AACR 2018) - "Also, IL-6 mediated signaling pathway such as JAK/STATIL-6 and AKT pathway, was activated by IL-6 and sIL-6. We suggest that IL-6 mediated signaling could mediate signaling regulates cytotoxic effect of Burkitt lymphoma cells by combined treatment of Danusertib and BKM120 as well as inflammatory effects may regulate the response of chemotherapeutic treatment."

Non-Hodgkin’s Lymphoma

Augmentation of danusertib's anticancer activity against melanoma by blockage of autophagy. (PubMed, Drug Deliv Transl Res) - "Thus, the induction of autophagy by danusertib appears to be a survival mechanism in melanoma cells that may counteract its anticancer effects. These findings suggest a novel strategy to enhance the anticancer efficacy of danusertib in melanoma by blocking autophagy."

Journal • Melanoma • Oncology • Solid Tumor

ERK-dependent IL-6 positive feedback loop mediates resistance against a combined treatment using danusertib and BKM120 in Burkitt lymphoma cell lines. (PubMed, Leuk Lymphoma) - "This study was conducted to define the synergistic effect of the PI3K inhibitor BKM120 with the pan-Aurora kinase inhibitor danusertib and the potential mechanism of resistance to the combined inhibitor treatment in Burkitt lymphoma cell lines. A blockade of ERK signaling with trametinib suppressed the combination treatment-induced ERK activation, reduced IL-6 mRNA expression, and downregulated IL-6R mRNA expression, resulting in an improvement in the antitumor effect. We stepwise treated Namalwa cells with both inhibitors using on-and-off treatment cycles and found that Namalwa cells gained chemoresistance by activating the ERK/IL-6 feedback loop, suggesting that the ERK-dependent IL-6 positive feedback loop can compensate for AKT inactivation and is closely associated with adaptive resistance and relapse."

Journal • Preclinical • Burkitt Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

[VIRTUAL] SETD2/KDM4A-MEDIATED H3K36ME3 LOSS IN CHRONIC MYELOID LEUKEMIA PATIENTS IN BLAST CRISIS CAN BE THERAPEUTICALLY TARGETED (EHA 2020) - "In the aforementioned cell lines, proteasomal inhibition by bortezomib, carfilzomib and ixazomib and AKA de-phosphorylation by Danusertib caused a time-dependent increase of annexin-V-positive cells by activating the mitochondrial apoptotic pathway as reflected by an increase in Bax expression and induction of the cleavage of caspase-3,-9 and PARP. Restoring physiological H3K36Me3 may help to improve the outcome of BC pts and might be an attractive opportunity to interfere with persistence of leukemic progenitors. Supported by AIRC (project 23001), AIL and Italian Ministry of Health, project GR-2016-02364880."

Clinical • Acute Myelogenous Leukemia • Chronic Myeloid Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • ABL1 • AURKA • CASP3 • CD34 • PARP • PARP1