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

A phase I study of the combination of ruxolitinib and the ERK1/2 inhibitor ulixertinib in previously treated myelofibrosis patients. (ASH 2025) - P1/2 | "These studies, if successful, will likely lead to future investigations combining JAK and ERKinhibitors not only in MF, but also in other diseases characterized by aberrant JAK-STAT signaling, andthus may have broad implications for an array of human diseases."

Clinical • P1 data • Myelofibrosis • Myeloproliferative Neoplasm • JAK2 • MKNK1 • PDGFRA • YBX1

Targeting the MEK/ERK Pathway to Suppress P-Glycoprotein and Reverse Carfilzomib Resistance in Multiple Myeloma. (PubMed, Int J Mol Sci) - "Carfilzomib (CFZ) is a cornerstone in the treatment of relapsed multiple myeloma (MM). At the IC50 concentration, both inhibitors reduced P-gp expression. In conclusion, combining CFZ with MAPK pathway inhibitors like cobimetinib or ulixertinib represents a promising strategy to overcome P-gp-mediated resistance in MM."

Journal • Hematological Malignancies • Multiple Myeloma • Oncology

Combinatorial targeting of avapritinib-driven MAPK activation in pediatric high-grade glioma (SNO 2025) - "Combinatorial treatment of pHGG models with MEK (selumetinib, trametinib), ERK (ulixertinib) and integrated stress/ERK inhibitors (ONC201, ONC206) in vitro eradicated pERK activity. A patient with an un-resected PDGFRα-mutant pHGG treated with avapritinib and selumetinib prior to progression demonstrated complete and ongoing tumor regression (12 months+). Considering sustained MAPK activation identified in our study, dual avapritinib-MAPK targeted treatment may be an effective approach for PDGFRΑ-driven pHGG."

Clinical • Brain Cancer • CNS Tumor • Glioma • High Grade Glioma • Pediatrics • Solid Tumor • MCL1 • PDGFRA

Combinatorial targeting of avapritinib-driven MAPK activation in pediatric high-grade glioma (WFNOS 2025) - "Combinatorial treatment of pHGG models with MEK (selumetinib, trametinib), ERK (ulixertinib) and integrated stress/ERK inhibitors (ONC201, ONC206) in vitro eradicated pERK activity. A patient with an un-resected PDGFRα-mutant pHGG treated with avapritinib and selumetinib prior to progression demonstrated complete and ongoing tumor regression (12 months+). Considering sustained MAPK activation identified in our study, dual avapritinib-MAPK targeted treatment may be an effective approach for PDGFRΑ-driven pHGG."

Clinical • Brain Cancer • CNS Tumor • Glioma • High Grade Glioma • Pediatrics • Solid Tumor • MCL1 • PDGFRA

Combinatorial targeting of avapritinib-driven MAPK activation in pediatric high-grade glioma (WFNOS 2025) - "Combinatorial treatment of pHGG models with MEK (selumetinib, trametinib), ERK (ulixertinib) and integrated stress/ERK inhibitors (ONC201, ONC206) in vitro eradicated pERK activity. A patient with an un-resected PDGFRα-mutant pHGG treated with avapritinib and selumetinib prior to progression demonstrated complete and ongoing tumor regression (12 months+). Considering sustained MAPK activation identified in our study, dual avapritinib-MAPK targeted treatment may be an effective approach for PDGFRΑ-driven pHGG."

Clinical • Brain Cancer • Pediatrics • Solid Tumor • MCL1 • PDGFRA

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

RAF-independent MEK mutations drive refractory histiocytic neoplasms but respond to ERK inhibition. (PubMed, Cancer Cell) - P | "Recently, the MEK1/2 inhibitor cobimetinib was FDA-approved for patients with adult histiocytoses...Four of five patients experienced objective responses to ulixertinib. These data reveal the impact of oncogenic MEK mutations in vivo, identify patients with likelihood of resistance to MEK inhibition, and nominate ERK inhibition to overcome resistance to MEK inhibition in histiocytoses."

Journal • Langerhans Cell Histiocytosis • Oncology • Rare Diseases

Activity of ulixertinib plus palbociclib in patients (Pts) with NRASQ61-mutant (mut) PD1 inhibitor refractory (PD1iR metastatic melanoma (MM)) (ESMO 2025) - P1 | "Conclusions In this preliminary analysis, ulixertinib plus palbociclib had a moderate clinical benefit not significantly higher than ulixertinib monotherapy; palbociclib may impair lymphocytic proliferation and offset its direct antitumor effect. Nevertheless, the regimen was well-tolerated in this heavily pretreated pt population."

Clinical • IO biomarker • Metastases • Melanoma • Oncology • Solid Tumor • NF1 • NRAS

NCI-MATCH: Targeted Therapy Directed by Genetic Testing in Treating Patients With Advanced Refractory Solid Tumors, Lymphomas, or Multiple Myeloma (The MATCH Screening Trial) (clinicaltrials.gov) - P2 | N=6452 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Dec 2025 ➔ Dec 2026 | Trial primary completion date: Dec 2025 ➔ Dec 2026

Biomarker • Trial completion date • Trial primary completion date • Bladder Cancer • Brain Cancer • Breast Cancer • Cervical Cancer • Colon Cancer • Colorectal Cancer • Endometrial Cancer • Esophageal Cancer • Gastric Cancer • Genito-urinary Cancer • Glioblastoma • Glioma • Head and Neck Cancer • Hematological Malignancies • Hormone Receptor Positive Breast Cancer • Kidney Cancer • Liver Cancer • Lung Cancer • Lymphoma • Melanoma • Multiple Myeloma • Oncology • Ovarian Cancer • Pancreatic Cancer • Prostate Cancer • Refractory Ovarian Cancer • Renal Cell Carcinoma • Skin Cancer • Solid Tumor • Thyroid Gland Carcinoma • Uterine Cancer • CD4 • MSI

Targeting acute myeloid leukemia resistance with two novel combinations demonstrate superior efficacy in TP53, HLA-B, MUC4 and FLT3 mutations. (PubMed, Biomed Pharmacother) - "Despite the advent of venetoclax-based regimens, resistance mechanisms remain a major clinical challenge, particularly in patients with high-risk mutations such as TP53, MUC4, HLA-B and FLT3. Here, we evaluate two rational combination therapies, LY3009120 (pan-RAF) plus sapanisertib (mTOR) (LS), and ruxolitinib (JAK1/2) plus ulixertinib (ERK) (RU), across ten AML cell lines and a zebrafish embryo xenograft model...Mutation response analyses and clustering highlighted TP53, MUC4, HLA-B and FLT3 as correlates of LS and RU sensitivity, supporting mutation-informed prioritization. Collectively, our results nominate LS and RU as promising candidates, particularly in AML with TP53, FLT3, HLA-B or MUC4 alterations, and motivate prospective validation in stratified AML cohorts."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • FLT3 • HLA-B • JAK1 • JAK2 • MUC4 • TP53

Sustained KRAS-MAPK Inhibition Induces Interferon-mediated Epithelial-to-Mesenchymal Transition and Reveals a Potential Therapeutic Opportunity Free (AACRPanCa 2025) - "On this basis, combining ulixertinib or the KRAS^G12D inhibitor MRTX1133 with the TROP2-directed antibody-drug conjugate sacituzumab govitecan markedly suppresses the growth of PDAC patient-derived xenografts (PDXs). Together, our study uncovers TRIM22 as a molecular link between interferon signaling and EMT and nominates TROP2 as a druggable vulnerability that can be co-targeted to augment the therapeutic efficacy of KRAS-MAPK pathway inhibitors."

Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Targeted Protein Degradation • KRAS • NFKBIA • TACSTD2 • TRIM22

RAD21-mediated epigenetic regulation promotes lung adenocarcinoma progression and sensitizes cancer cells to ERK-targeted therapy. (PubMed, Cancer Lett) - "Our findings establish RAD21-mediated epigenetic regulation as a novel mechanism driving LUAD progression. The efficacy of ulixertinib in suppressing cancer metastasis in preclinical models highlights its translational potential for LUAD therapy."

Journal • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS • RAD21

Synergy Between second-generation FLT3 inhibitors and the ERK1/2 inhibitor Ulixertinib in FLT3-ITD-mutated acute myeloid leukemia (AML) cells. (PubMed, Med Oncol) - "We screened datasets associated with Gilteritinib and Quizartinib in the Gene Expression Omnibus (GEO) database for enrichment analysis and validated potential key pathways that may limit their therapeutic efficacy through qPCR and Western blot. Transcriptome sequencing revealed that these synergistic effects may stem from the regulation of gene expression such as PKD1, NR2E3, KDF1, and PRSS8 as well as modulation of ion channel activity. This in vitro study identifies aberrant activation of the RAS/MAPK pathway as a critical factor limiting the efficacy of FLT3 inhibitors in FLT3-ITD-positive AML and demonstrates the potent synergistic effects of Ulixertinib combined with FLT3 inhibitors in FLT3-ITD-positive AML cells, providing a novel therapeutic strategy for AML."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • FLT3 • NR2E3 • PKD1 • PRKD1 • PRSS8

Development of a prognostic risk model for predicting biochemical recurrence-free survival in patients with prostate cancer based on lysine acetylation. (PubMed, Transl Androl Urol) - "Drugs such as cisplatin, MK-1775, and ulixertinib were identified as potential therapeutic agents for PCa. Five BCR-free-related prognostic genes were identified as potential therapeutic targets. Additionally, a BCR-free-related prognostic risk model was developed, offering a robust tool for predicting BCR-free survival in patients with PCa."

Journal • Genito-urinary Cancer • Oncology • Prostate Adenocarcinoma • Prostate Cancer • Solid Tumor • PLS3

Ulixertinib/Palbociclib in Patients With Advanced Pancreatic and Other Solid Tumors (clinicaltrials.gov) - P1 | N=45 | Recruiting | Sponsor: UNC Lineberger Comprehensive Cancer Center | Trial primary completion date: Aug 2025 ➔ Jul 2026

Trial primary completion date • Melanoma • Oncology • Pancreatic Cancer • Solid Tumor • BRAF • CA 19-9 • HRAS • KRAS • NF1 • NRAS

Advances in ERK1/2 inhibition: a medicinal chemistry perspective on structure and regulation. (PubMed, J Enzyme Inhib Med Chem) - "Several molecules-such as SCH772984, SCH900353, ulixertinib (BVD-523), CC-9003, KO-947, AZD0364, norathyriol, and FR180204-are currently in preclinical or clinical trial stages. This review also highlights recent advances in the design and synthesis of ERK inhibitors, emphasising their structural uniqueness and potential to inhibit mutant forms of ERK1/2. Finally, we discuss future directions for the development of ERK1/2 inhibitors as FDA-approved cancer therapeutics."

Journal • Review • Oncology • MAPK1 • MAPK3

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 primary completion date: Dec 2025 ➔ Dec 2026 | Trial completion date: Dec 2025 ➔ Dec 2026

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

ERK1/2 Signaling in Intrahepatic Cholangiocarcinoma: From Preclinical Advances to Therapeutic Strategies. (PubMed, Biology (Basel)) - "In particular, PD901 and U0126 effectively reduce iCCA cell proliferation and invasion. Furthermore, Ulixertinib has shown a favorable therapeutic index and encouraging activity in clinical trials involving advanced solid tumors, including iCCA, paving the way for a new therapeutic approach targeting ERK1/2. Nevertheless, the heterogeneous and dynamic molecular landscape of iCCA, often accompanied by drug resistance, presents significant therapeutic challenges. We underscore how targeting the ERK1/2 pathway could represent a cornerstone within a multifaceted therapeutic strategy, fostering the development of personalized treatment approaches and improving clinical outcomes in iCCA patients."

Journal • Preclinical • Review • Biliary Cancer • Cholangiocarcinoma • Oncology • Solid Tumor

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