ulixertinib (BVD-523) / BioMed Valley Discoveries - LARVOL DELTA

DUAL PATHWAY TARGETING IN AML: BMP INHIBITION FOR DE NOVO DISEASE AND ERK INHIBITION FOR THERAPY-RESISTANCE (EHA 2025) - "Key signaling pathways in the AML-M5 cell line THP1 studied with LDN193189 (LDN) and the ERK1/2 inhibitor BVD-523 (BVD) were evaluated in combination treatment with Ara-C in therapy sensitive and resistance AML cell lines. Our data support BMP inhibition as a viable strategy for de novo AML and highlight ERK inhibition as a promising approach to overcome therapy resistance in AML."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • ABCB1 • ABCG2 • BAX • BCL2 • CCND1 • CDKN1A • GLI2 • ID2

Genes driving three-dimensional growth of immortalized cells and cancer. (PubMed, Cell Death Dis) - "Inhibition of MAPK1 by Ulixertinib, an orally active MAPK1 inhibitor, led to human bladder cancer growth inhibition in both 3D in vitro and in vivo models. In summary, screening for genes specifically driving 3D growth in immortalized cells may provide targets for both prevention and early therapy in bladder and other cancers while potentially limiting therapeutic toxicity."

Journal • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • MAPK1

Independent and synergistic roles of MEK-ERK1/2 and PKC pathways in regulating functional changes in vascular tissue following flow cessation. (PubMed, J Mol Cell Cardiol Plus) - "Rat basilar arteries were cultured for 48 h with selective inhibitors targeting MEK (Trametinib), PKC (RO-317549) and their downstream ERK (Ulixertinib) and NF-kB (BMS 345541). MEK inhibition is effective early, while PKC inhibition remains effective when applied later. The additive effects observed with combined MEK and PKC inhibition indicate parallel and functionally independent pathway activation during ETB receptor upregulation."

Journal • Cardiovascular

Disrupting the FramewERK - Constitutive ERK Deletion Regulates Monocyte Differentiation and Fibrosis Progression (ATS 2025) - P2 | "Additionally, we generated mice harboring a conditional deletion of Erk2 in MDMs by crossing Erk2fl/fl (Mapk1fl/fl) with mice containing a tamoxifen-inducible Cre driven by the Cx3cr1 promoter. Mice were exposed to saline or bleomycin (1.5 U/kg)... These observations suggest that ERK2 is required for MDM differentiation into resident-like alveolar macrophages, and the absence of ERK2 mediates a persistence and increased number of MDMs that mediate significantly greater severity and progression of pulmonary fibrosis."

Fibrosis • Immunology • Pulmonary Disease • Respiratory Diseases • CX3CR1 • MAFB • MAPK1 • STAT6

Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders (The Pediatric MATCH Screening Trial) (clinicaltrials.gov) - P2 | N=1376 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | N=2316 ➔ 1376 | Trial completion date: Jun 2025 ➔ May 2026 | Trial primary completion date: Jun 2025 ➔ Mar 2025

Biomarker • Enrollment change • Trial completion date • Trial primary completion date • Brain Cancer • CNS Tumor • Embryonal Tumor • Ependymoma • Ewing Sarcoma • Germ Cell Tumors • Glioma • Hematological Malignancies • Hepatoblastoma • Langerhans Cell Histiocytosis • Lymphoma • Malignant Glioma • Medulloblastoma • Nephrology • Neuroblastoma • Non-Hodgkin’s Lymphoma • Oncology • Osteosarcoma • Pediatrics • Rhabdoid Tumor • Rhabdomyosarcoma • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • Wilms Tumor • BRAF

CanSeer: a translational methodology for developing personalized cancer models and therapeutics. (PubMed, Sci Rep) - "To exemplify, three use cases involving paired samples, unpaired samples, and cancer samples only, of lung squamous cell carcinoma (LUSC) patients are provided. CanSeer reveals the effectiveness of repositioned drugs along with the identification of several novel LUSC treatment combinations including Afuresertib + Palbociclib, Dinaciclib + Trametinib, Afatinib + Oxaliplatin, Ulixertinib + Olaparib, etc."

Journal • Preclinical • Non Small Cell Lung Cancer • Oncology • Squamous Cell Carcinoma

Unravelling NK cell subset dynamics and specific gene signatures post-ibrutinib therapy in chronic lymphocytic leukaemia via single-cell transcriptomics. (PubMed, BMC Cancer) - "The CLL_NK subset plays a crucial role in the development and progression of CLL. The CNI, derived from its key genes, holds promise as a predictor of immune therapeutic responses, highlighting the significance of CLL_NK subset dynamics and their genetic underpinnings in CLL management."

Gene Signature • IO biomarker • Journal • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • Richter's Syndrome

Interactions between CD8+ T cells and tumor cells decode tumor heterogeneity and provide treatment recommendations for colorectal cancer (AACR 2025) - "Finally, using the oncoPredict algorithm, we predicted chemotherapy drug sensitivity and discovered that C2 showed a superior response to dasatinib and AZ960, while exhibiting resistance to ulixertinib. This study provides critical insights into the complex interactions between CD8+ T cells and CRC cells, highlighting their pivotal role in tumor heterogeneity. This study provides critical insights into the complex interactions between CD8+ T cells and CRC cells, highlighting their pivotal role in tumor heterogeneity. Leveraging these findings, we developed a novel classification system for CRC patients that captured TME heterogeneity and stratified patients into distinct groups. This system lays a foundation for personalized therapeutic strategies based on tumor-immune dynamics, offering significant potential to improve prognosis for CRC patients."

Heterogeneity • Tumor cell • Colorectal Cancer • Oncology • Solid Tumor • CD8

Experimental Insights and Recommendations for Successfully Performing Cerebral Microdialysis With Hydrophobic Drug Candidates. (PubMed, Clin Transl Sci) - "The present study reports the outcomes of comprehensive microdialysis investigations in rodents, focusing on three hydrophobic compounds: actinomycin D, selinexor, and ulixertinib. This review encompassed keyword-driven PubMed-indexed publications on microdialysis from 1970 to 2024, providing a broader context for the challenges and solutions associated with the technique. By integrating empirical results with practical recommendations, this study offers a comprehensive resource aimed at advancing the application of cerebral microdialysis in preclinical drug development, particularly for compounds with challenging physicochemical properties."

Journal • Review

Novel tyrosine kinase/MEK inhibitor combinations impair the viability and invasive potential of TNBC cell lines (AACR 2025) - "We identified several cytokines secreted in response to the pan-Raf inhibitor CCT196969, the MEK inhibitor (MEKi) trametinib and the ERK inhibitor (ERKi) ulixertinib such as FGF-basic, FGF-19, MIF and angiogenin. Lastly, the trametinib/ALW-II-41-27 combination revealed a significant reduction in cell migration and invasion compared to trametinib treatment alone. These findings indicate that ponatinib and ALW-II-41-27 combined with MAPKi could be a promising novel therapeutic approach for TNBC."

Preclinical • Oncology • Triple Negative Breast Cancer • ALK • ERBB3 • FGF19 • FGFR1 • FGFR3 • HER-2

Biomed Valley Discoveries Announces First Patient Dosed in Phase 1/2 Combination Study of Ulixertinib with Ruxolitinib (Jakafi) in Patients with Myelofibrosis (GlobeNewswire) - "Biomed Valley Discoveries...announced that the first patient has been dosed in a Phase 1/2 combination study of ulixertinib, BVD’s highly selective, first-in-class ERK 1/2 inhibitor with ruxolitinib, a JAK1/JAK2 inhibitor for the treatment of myelofibrosis, a rare type of bone marrow cancer that disrupts the body’s normal production of blood cells....The Phase 1/2 study (NCT06773195) will evaluate the safety, tolerability and efficacy of ulixertinib in combination with ruxolitinib in adult patients 18 years and older who exhibit persistent disease after at least three months of receiving a stable dose of ruxolitinib monotherapy. Patients with primary myelofibrosis, post-essential thrombocythemia (ET) myelofibrosis, post-polycythemia vera (PV) myelofibrosis, or post-pre-fibrotic myelofibrosis are eligible for the trial."

Trial status • Myelofibrosis

Identification and Validation of Gastric Adenocarcinoma Prognosis Features Based on Neutrophil-Related Genes. (PubMed, JCO Precis Oncol) - "In summary, on the basis of expression levels of NRGs, a new prognostic model was established. NHLRC3, PTPRJ, RTEL1, ST6GALNAC2, HRNR, HP, and MCEMP1 were valid candidate biomarkers that may help personalize prognostic predictions and serve as references for clinical studies."

IO biomarker • Journal • Gastric Adenocarcinoma • Gastric Cancer • Oncology • Solid Tumor • HRNR • RTEL1

RRAS and RRAS2 hotspot mutations as novel actionable oncogenic drivers in lung adenocarcinoma (ELCC 2025) - P1 | "Growth of HBEC and Ba/F3 cells expressing RRAS or RRAS2 mutations was sensitive to inhibitors of ERK1/2 (ulixertinib, SCH772984), MEK1/2 (binimetinib), and RAS (RMC-6236). Our findings suggest that patients with RRAS/RRAS2-mutant tumors are likely to derive benefit from RMC-6236 (NCT05379985). Finally, the results are relevant beyond LUAD, as RRAS2 Q72L mutations are also seen in endometrial and ovarian cancers, as well as germ cell tumors."

Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • HRAS • KRAS • MAP2K1 • NRAS • RRAS2

Expression of MCCC2 in glioma cells and preliminary verification of poor prognosis. (PubMed, Biomark Med) - "Ulixertinib, an ERK inhibitor, was shown to hinder the proliferation, migration, and invasion of GBM cells and counteract the regulatory impact of MCCC2 overexpression on GBM cells. This investigation revealed that suppressing MCCC2 expression impedes the proliferation, migration, and invasion of GBM cells and promotes GBM cell apoptosis by curtailing ERK expression and phosphorylation. This discovery implies that MCCC2 might serve as a potential biological target for anti-GBM therapy, laying the groundwork for future research in this field."

Journal • Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Oncology • Solid Tumor • MAPK1 • MCCC2

A first-in-class selective inhibitor of ERK1/2 and ERK5 overcomes drug resistance with a single-molecule strategy. (PubMed, Signal Transduct Target Ther) - "SKLB-D18 demonstrated excellent tolerability in mice and demonstrated superior in vivo anti-tumor efficacy, not only exceeding the existing clinical ERK1/2 inhibitor BVD-523, but also the combination regimen of BVD-523 and the ERK5 inhibitor XMD8-92. Mechanistically, we showed that SKLB-D18, as an autophagy agonist, played a role in mammalian target of rapamycin (mTOR)/70 ribosomal protein S6 kinase (p70S6K) and nuclear receptor coactivator 4 (NCOA4)-mediated ferroptosis, which may mitigate multidrug resistance."

Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • KRAS • mTOR • NCOA4 • RPS6

Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders (The Pediatric MATCH Screening Trial) (clinicaltrials.gov) - P2 | N=2316 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Sep 2027 ➔ Jun 2025 | Trial primary completion date: Sep 2027 ➔ Jun 2025

Biomarker • Trial completion date • Trial primary completion date • Brain Cancer • CNS Tumor • Embryonal Tumor • Ependymoma • Ewing Sarcoma • Germ Cell Tumors • Glioma • Hematological Malignancies • Hepatoblastoma • Hepatology • Langerhans Cell Histiocytosis • Lymphoma • Malignant Glioma • Medulloblastoma • Nephrology • Neuroblastoma • Non-Hodgkin’s Lymphoma • Oncology • Osteosarcoma • Pediatrics • Rhabdoid Tumor • Rhabdomyosarcoma • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • Wilms Tumor • BRAF

RRAS and RRAS2 are actionable oncogenic drivers in NSCLC (IASLC-TTLC 2025) - P1 | "Growth of HBEC and Ba/F3 cells expressing RRAS or RRAS2 mutations showed enhanced sensitivity to inhibitors of ERK1/2 (ulixertinib and SCH772984), MEK1/2 (binimetinib), and RAS (RMC-6236). RRASQ87L and RRAS2Q72L are oncogenic in NSCLC and are mutually exclusive with other known lung cancer drivers. Constitutive activation of RRAS and RRAS2 elevated both the MAPK and PI3K-AKT axes and confers susceptibility to targeted inhibition of the MAPK pathway. Notably, the novel pan-RAS inhibitor RMC-6236 diminished RRAS and RRAS2-driven tumor growth in vivo."

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • HRAS • KRAS • MAP2K1 • NRAS • RRAS2

EAY131-Z1L: Testing BVD-523FB (Ulixertinib) as Potentially Targeted Treatment in Cancers With Genetic Changes (MATCH - Subprotocol Z1L) (clinicaltrials.gov) - P2 | N=35 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Mar 2025 ➔ Dec 2025 | Trial primary completion date: Mar 2025 ➔ Dec 2025

Trial completion date • Trial primary completion date • Hematological Malignancies • Lymphoma • Multiple Myeloma • Oncology • Solid Tumor • BRAF

A Study of Ruxolitinib in Combination With Ulixertinib in People With Myelofibrosis (clinicaltrials.gov) - P1/2 | N=37 | Recruiting | Sponsor: Memorial Sloan Kettering Cancer Center

New P1/2 trial • Myelofibrosis

Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders (The Pediatric MATCH Screening Trial) (clinicaltrials.gov) - P2 | N=2316 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Recruiting ➔ Active, not recruiting

Biomarker • Enrollment closed • Brain Cancer • CNS Tumor • Embryonal Tumor • Ependymoma • Ewing Sarcoma • Germ Cell Tumors • Glioma • Hematological Malignancies • Hepatoblastoma • Hepatology • Langerhans Cell Histiocytosis • Lymphoma • Malignant Glioma • Medulloblastoma • Nephrology • Neuroblastoma • Non-Hodgkin’s Lymphoma • Oncology • Osteosarcoma • Pediatrics • Rhabdoid Tumor • Rhabdomyosarcoma • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • Wilms Tumor • BRAF

Adaptation of Chronic Lymphocytic Leukemia to Ibrutinib Is Mediated By Epigenetic Plasticity of Residual Disease and By-Pass Signaling Via MAPK Pathway (ASH 2024) - "Administration of ulixertinib, an ERK1/2 kinase inhibitor, in combination with ibrutinib significantly delayed tumor growth in vitro and in vivo. Adaptation to BTK inhibition in CLL is mainly epigenetically driven and selects MRD cells with BCRlow/ERKhigh phenotype. RAS-RAF-MEK-ERK proved to be a vulnerability of MRD."

IO biomarker • Residual disease • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • CD40 • IL4 • PLCG2

Effects of ERK1/2 Inhibitors on the Growth of Acute Leukemia Cells. (PubMed, Anticancer Res) - "ERK1/2 inhibitors may serve as novel molecular-targeted drugs for treating leukemia with NRAS mutations."

Journal • Acute Myelogenous Leukemia • CNS Tumor • Hematological Malignancies • Leukemia • Neuroblastoma • Oncology • Solid Tumor • MYC • NRAS

Enhancing therapeutic approaches in high-grade gliomas: synergistic effects of LSD1 and kinase inhibition (SNO 2024) - "Pharmacological LSD1 inhibition was tested using NCD38 or bomedemstat in HGG models and normal human astrocytes (NHA). The effects of combining LSD1 inhibitors with kinase inhibitors (osimertinib, afatinib, and ulixertinib) on cell viability were evaluated... GSEA revealed LSD1 expression was enriched for gene sets involved in kinase signaling processes. Increased phosphorylated ERK1/2 levels were observed following NCD38 treatment in MDA-GSC17, as shown by RPPA and western blot analyses. The LSD1 inhibitor, NCD38, increased phospho-ERK1/2 levels (72% increase from baseline), while co-treatment with osimertinib mitigated this effect."

Brain Cancer • CNS Tumor • Diffuse Intrinsic Pontine Glioma • Glioblastoma • Glioma • Malignant Glioma • Oncology • Solid Tumor • KDM1A

Ibrutinib Increases Phosphorylation of the Src-Erk1/2 Signaling Pathway in Human Atrial-Specific Cardiomyocytes Derived from Induced Pluripotent Stem Cells (AHA 2024) - "In hiPSC-aCMs, inhibition of CSK by ibrutinib results in increased arrhythmogenic behavior through Erk1/2-dependent phosphorylation. The downstream mechanisms by which this occurs remain unknown and represent novel potential target(s) for AF therapeutics."

Atrial Fibrillation • Cardiovascular • Hematological Malignancies • Oncology • CSK

Inflammasome complex genes with clinical relevance suggest potential as therapeutic targets for anti-tumor drugs in clear cell renal cell carcinoma. (PubMed, Open Life Sci) - "Furthermore, our study revealed the potential of inflammasome complex genes as predictive markers for patient responses to various anti-tumor drugs, including Osimertinib, Ulixertinib, Telomerase Inhibitor IX, and GSK2578215A. These findings have significant clinical implications and offer opportunities for guiding treatment strategies and improving patient outcomes of ccRCC."

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