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

Combination Therapies with CDK4/6 Inhibitors to Treat KRAS-mutant Pancreatic Cancer. (PubMed, Cancer Res) - P1 | "Based on these findings, a Phase I clinical trial was initiated to evaluate the ERKi ulixertinib in combination with the CDK4/6i palbociclib in patients with advanced PDAC (NCT03454035). Additionally, genes whose loss imparts a survival advantage were identified (e.g., RB1, PTEN, FBXW7), suggesting possible resistance mechanisms to CDK4/6 inhibition. In summary, this study has identified novel combinations with CDK4/6i that may have clinical benefit to PDAC patients."

Combination therapy • Journal • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • CDK2 • CDKN2A • FBXW7 • KRAS • MYC • PTEN • RB1

BVD-523FB (Ulixertinib) in Patients with Tumors with BRAF Fusions, or with Non-V600E, Non-V600K BRAF Mutations: Results from the NCI-MATCH ECOG-ACRIN Trial (EAY131) Sub-protocol EAY131-Z1L (AACR 2022) - "BVD-523FB (ulixertinib) had no demonstrable evidence of clinical activity in this small, heavily pre-treated population of patients with tumors harboring BRAF fusions, or with non-V600E, non-V600K BRAF mutations"

Clinical • Gastrointestinal Cancer • Lung Cancer • Melanoma • Oncology • Solid Tumor • BRAF • MAPK1

Ulixertinib in patients with tumors with MAPK pathway alterations: Results from NCI-COG Pediatric MATCH trial Arm J (APEC1621J). (ASCO 2022) - P2 | "The pediatric RP2D of ulixertinib was established as 260 mg/m2/dose PO BID. There were no objective responses in this cohort of children and young adults with treatment-refractory tumors with activating MAPK alterations. Clinical benefit of prolonged disease control was observed in 3 patients with BRAF-altered gliomas and glioneuronal tumors."

Clinical • Anorexia • Brain Cancer • CNS Tumor • Fatigue • Glioma • Hematological Malignancies • Lymphoma • Musculoskeletal Diseases • Oncology • Orthopedics • Pediatrics • Rhabdomyosarcoma • Sarcoma • Solid Tumor • ARAF • BRAF • GNA11 • GNAQ • HRAS • KRAS • MAP2K1 • MAPK1 • NF1 • NRAS

Bulk and single cell RNA sequencing data reveal lactylation-related gene signatures for prognosis and immunity in cervical cancer. (PubMed, Braz J Med Biol Res) - "Furthermore, bioinformatics analyses further indicated that the high-risk group was associated with a poorer prognosis, pro-tumorigenic pathways, and immunosuppression, and was sensitive to ulixertinib, dasatinib, nutlin-3a, and trametinib. In conclusion, the lactylation-related gene risk model could accurately and independently predict the prognosis of CC patients, providing insights into therapeutic strategies for CC patients. These bioinformatics-based findings are exploratory and warrant further validation in preclinical and clinical settings."

Gene Signature • Journal • Cervical Cancer • Oncology • Solid Tumor • ITGA5

LCCC1736: Ulixertinib/Palbociclib in Patients With Advanced Pancreatic and Other Solid Tumors (clinicaltrials.gov) - P1 | N=45 | Recruiting | Sponsor: UNC Lineberger Comprehensive Cancer Center | Trial completion date: Nov 2026 ➔ Feb 2028 | Trial primary completion date: Jul 2026 ➔ Feb 2028

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

ERK1/2 Inhibitor Ulixertinib in Pan-cancer Patients with BRAF Fusions or Non-V600E/K Mutations: Results from the NCI-MATCH ECOG-ACRIN Trial (EAY131) Subprotocol Z1L. (PubMed, Clin Cancer Res) - "Ulixertinib had no demonstrable evidence of clinical activity in this small, heavily pretreated population of patients with tumors harboring BRAF fusions, or with non-V600E, non-V600K BRAF mutations."

Journal • Lung Cancer • Melanoma • Oncology • Solid Tumor • BRAF

A comprehensive study based on large-sample multi-omics integration and machine learning to decode mitochondria-associated genes: from digestive tract tumours to gastric cancer. (PubMed, Front Immunol) - "Dysregulated expression of LACTB2 can affect the prognosis of GC patients, and Afatinib and Ulixertinib may play a significant role in targeting LACTB2 in the treatment of GC patients. An excellent early blood diagnostic model for GC was constructed based on the upstream miRNA of LACTB2. Our study provides new insights into the differential expression and pathogenesis of LACTB2 in digestive tract tumours, particularly its prognostic and diagnostic value in GC."

Journal • Gastric Cancer • Oncology • Solid Tumor • LACTB

Erk inhibitors intercept Erk-mediated negative feedback while imposing cell-cycle arrest and activating p38. (PubMed, iScience) - "Provision of either BVD523, GDC0994, SCH772984, ASN007, or Temuterkib, led to strong phosphorylation of Erks, suggesting that all inhibitors intercepted Erks-mediated negative feedback activity...Exposure to BVD523 caused dramatic changes in the phosphoproteome. Thus, the application of Erk's inhibitors should be accompanied by agents that prevent pathway re-activation."

Journal • Oncology

A dataset supporting Combinatorial Proteome Integral Solubility/Stability Alteration Analysis (CoPISA). (PubMed, Sci Data) - "The dataset includes two AML drug pairs (LY3009120-sapanisertib and ruxolitinib-ulixertinib) applied to four AML cell lines (MOLM-13, MOLM-16, SKM-1, and NOMO-1) under control, single-agent, and combination conditions in both lysate and intact-cell formats. All data are publicly available through the PRIDE repository (PXD066812) together with analysis code, enabling independent reanalysis and method development. This dataset provides a benchmark resource for studying proteome responses to drug combinations, comparing lysate and intact-cell perturbation profiles, developing computational approaches for combinatorial target inference, and supporting training in computational proteomics."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

Innovative precision-guided MAPK inhibition: expanding therapeutic benefits in pediatric glioma (ISPNO 2026) - "Mitogen-activated protein kinase kinase (MEK; trametinib/pimasertib) or extracellular signal-regulated kinase (ERK; ulixertinib) inhibition was combined with rapidly accelerated fibrosarcoma (RAF; tovorafenib) or phosphatidylinositol 3-kinase (PI3K; paxalisib) inhibition to compare vertical MAPK versus horizontal MAPK/PI3K pathway blockade. This study demonstrates that dual MEK and RAF inhibition with clinically relevant, brain-penetrant agents is highly effective against HGG and DMG tumors, independent of MAPK status. Studies ascertaining relevant biomarkers within this setting are currently underway to guide enrollment of children into the OPTIMISE clinical trial."

Clinical • Brain Cancer • Diffuse Midline Glioma • Fibrosarcoma • Glioma • High Grade Glioma • Pediatrics • Sarcoma • Solid Tumor

Compensatory Receptor Tyrosine Kinase Signaling Reactivates the RAF–MEK–ERK pathway causing resistance to MEK-inhibition in Glioblastoma. (EACR 2026) - "Treatment efficacy was assessed in 2D using Alamar Blue and crystal violet assays, and in 3D spheroid models, with Bliss scores calculated to determine drug synergy.Result and MEK inhibition with trametinib or selumetinib induced adaptive kinase network remodeling across all GB models, characterized by MEK–AKT crosstalk and enhanced JNK/c-JUN activity...Interestingly, ERK blockade with ulixertinib produced a comparable compensatory response. Combining MEK with JNK inhibition (SP600125) to block parallel activated JNK signaling synergistically reduced cell viability, but did not prevent MEK inhibitor induced MEKSer221 hyperphosphorylation. This study outlines a mechanistic strategy for selecting SMIs to overcome MEK-inhibitor resistance in pdGB models."

Brain Cancer • Glioblastoma • Solid Tumor

Multi-sampling allows intra-tumoral heterogeneity querying and vulnerability profiling in glioblastoma. (PubMed, Neuro Oncol) - "This work demonstrates the regional heterogeneity of therapeutic vulnerabilities in GBM ex vivo, showing various drugs with tumor-wide or MRI-enhancement informed activity. These findings offer preclinical bases of numerous monotherapies and drug combinations for future clinical trial design."

Heterogeneity • IO biomarker • Journal • Brain Cancer • Glioblastoma • Oncology • Solid Tumor • BCL2

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

SHP2 Inhibition Reveals Compensatory PI3K-AKT Activation in KRAS-Driven Pancreatic Cancer: Discovery of SDUY104 and Rational Approaches for Combination Therapy. (PubMed, J Med Chem) - "Combining SDUY104 with an ERK inhibitor Ulixertinib produced synergistic antiproliferative activity via enhanced MAPK suppression. In a PANC-1 xenograft model, combination of SDUY104 with BKM-120 exhibited superior antitumor activity compared to either monotherapy. Collectively, this study identifies a potent SHP2 allosteric inhibitor and delineates a critical compensatory signaling mechanism underlying resistance to SHP2-targeted therapy, providing proof-of-concept support for pancreatic cancer treatment."

Journal • Oncology • Pancreatic Cancer • Solid Tumor • KRAS

Characterization of intrinsic and acquired resistance to KRASG12C inhibitors across a broad collection of cancer cell line models (AACR 2026) - "Although PTEN loss was restricted to OV56, both OV56 and SW1573 were resistant to inhibitors of various MAPK pathway components, including RAF (tovorafenib, belvarafenib), MEK (trametinib), and ERK (ulixertinib), suggesting MAPK pathway independence. Cross-resistance to adagrasib, sotorasib and divarasib was also observed in the acquired resistant models.Intrinsically KRASG12C inhibitor-resistant cell lines, along with acquired resistant models, represent valuable systems for evaluating next-generation KRAS inhibitors and identifying new drug combinations to optimize therapeutic benefit of KRASG12C inhibitors in patients."

Preclinical • Oncology • KRAS • PTEN

Prolonged KRAS-MAPK inhibition activates interferon signaling to promote cellular plasticity and uncover novel targets for combination therapy (AACR 2026) - "Combining ulixertinib or the KRAS inhibitor MRTX1133 with the TROP2-directed antibody-drug conjugate sacituzumab govitecan effectively suppressed growth of PDAC patient-derived xenografts. This study highlights TRIM22's role in linking interferon signaling with EMT and identifies TROP2 as a therapeutic vulnerability to overcome acquired resistance."

Combination therapy • Oncology • KRAS • NFKBIA • TACSTD2 • TRIM22

Oncogenic KRAS mutations drive estrogen independence and induce targetable vulnerabilities in treatment-resistant ER+ breast cancer (AACR 2026) - "In both cell lines, KRASG12V drove resistance to estrogen deprivation (mimicking aromatase inhibitor treatment) and total ER blockade (estrogen deprivation + Fulvestrant), while parental cell growth stalled...Treatment with the RAS(ON) multi-selective inhibitor daraxonrasib completely abrogated the estrogen-independent proliferation of KRASG12V cells. To determine signaling dependencies downstream of KRASG12V we treated cells with the mTORC1-selective inhibitor RMC-5552 (mTORC1i) or the ERK1/2 inhibitor ulixertinib (ERKi)...We are actively investigating the underlying mechanisms and applying CRISPR knockout screens and RNA-seq to identify other vulnerabilities. Given the recent surge of clinically viable RAS inhibitors, these findings may inform new combination strategies for a highly refractory subset of ER+ breast cancer."

Late-breaking abstract • Breast Cancer • Estrogen Receptor Positive Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • ER • HRAS • KRAS • NF1 • NRAS

Ulixertinib in Treating Patients With Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With MAPK Pathway Mutations (A Pediatric MATCH Treatment Trial) (clinicaltrials.gov) - P2 | N=20 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Mar 2026 ➔ Mar 2027

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

FGFR3 altered bladder cancer exhibits a lineage-dependent vulnerability (AACR 2024) - "Moreover, the synergy in FGFR3-mutant cells was superior to that of SHP2 inhibitor SHP099 or the ERK inhibitor BVD-523...By contrast, Sel120+Erdafitinib induced complete responses in 8/10 mice compared to 6/10 mice for SHP099+Erdafitinib...Our results suggest an immediate and promising benefit in combining either CDK8/19 or SHP2 inhibitors with Erdafitinib in treating patients with FGFR3 alteration driven bladder cancers. Furthermore, we identified a strategy in targeting lineage modulators as sensitizers to existing therapies."

Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • FGFR3 • GATA3 • PPARG

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

Polyisoprenylated cysteinyl amide inhibitors: Effects on RAS signaling pathway intermediates and viability of mutant KRAS African American lung cancer cell line (AACR 2024) - "The EC50 values for the PCAIs NSL-YHJ-2-27 and NSL-AB-45 were 4.1 ± 0.3 and 5.5 ± 0.1 μM, respectively, compared to Gefitinib (EGFR), Sotorasib (KRASG12C), Dabrafenib (BRAF), Selumetinib (MEK1/2), Ulixertinib (ERK1/2) and Ipatasertib (AKT) whose EC50 values were 83 ± 12.9 μM, 38 ± 5.5 μM, 33 ± 1.2 μM, 71 ± 5.3 μM, 11 ± 0.2 μM, 12 ± 1.0 μM, respectively. Future work will determine the effects of co-treating cells with the PCAIs and the respective kinase inhibitors on cell viability and PCAIs-induced phosphorylation of the kinases. Supported by grants U54CA233396, U54CA233444, and U54CA233465 from the National Institutes of Health (NIH)/National Cancer Institute (NCI) and the Norris Comprehensive Cancer Center core grant, award number P30CA014089 from the NIH/NCI"

Preclinical • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • BRAF • EGFR • KRAS • MAP2K1

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

Solubility based mechanistic profiling of combinatorial drug therapy. (PubMed, Nat Commun) - "We applied CoPISA to two rationally designed AML drug pairs, LY3009120-sapanisertib (LS) and ruxolitinib-ulixertinib (RU), previously identified as the most effective and least toxic combinations among many candidates and validated in AML cell lines, patient-derived samples and zebrafish xenograft models. Network analysis demonstrated that a substantial fraction of AML-associated proteins targeted by CoPISA are unique to combinations, including DNMT3A, NPM1, and TP53. By uncovering a mechanistic layer beyond classical synergy, CoPISA provides a robust framework for the precision-guided design of combinatorial therapies in heterogeneous cancers."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • DNMT3A • NPM1 • TP53

ERK1/2-targeted Cancer therapies: Recent advances, potential drug resistance, and applicability analysis of emerging technologies. (PubMed, Bioorg Chem) - "Firstly, although first-generation ATP-competitive inhibitors such as Ulixertinib have shown antitumor activity in early-phase trials, their efficacy varies widely across patient populations and is often accompanied by mechanism-based toxicities (including rash and diarrhea), highlighting a substantial disconnection between preclinical predictions and clinical outcomes...Furthermore, it highlights emerging technological advances, including innovative modalities that address limitations of traditional ATP-competitive inhibitors, such as targeted protein degradation (TPD) approaches. Collectively, this review seeks to outline a clearer roadmap toward realizing the full therapeutic potential of ERK1/2-targeted interventions in cancer treatment."

Journal • Review • Oncology • Targeted Protein Degradation • MAPK1

Targeting BRAF Fusions with Pan-RAF Inhibitors Highlights Fusion Type–Associated Heterogeneity in Drug Responses and the Need for Combination Therapy with MEK/ERK Inhibitors (IASLC-TTLC 2026) - P1 | "These cell lines were also resistant to the pan-RAS inhibitor RMC-6236 and showed differential sensitivity to pan-RAF inhibitors, with BRAF ex8/9 fusions being the most responsive compared to ex10/11: specifically, average IC50 values for growth inhibition by exarafenib were AGK::BRAFex8: 66nM; AGAP3::BRAFex9: 60nM; TRIM24::BRAFex10: 321nM; SND1::BRAFex11: 1921nM. Similar patterns of sensitivity were observed with other pan-RAF inhibitors (LY3009120, belvarefinib, encorafenib). All CRISPR lines were exquisitely sensitive to MEK1/2 (binimetinib, cobimetinib) and ERK1/2 (ulixertinib) inhibitors, compared to isogenic control cells...We also found that the combination of exarafenib and osimertinib is effective in vivo for EGFR-mutated NSCLC with acquired BRAF fusion. Exarafenib is currently in clinical trials for BRAF- and NRAS-mutant solid tumors (NCT04913285)."

Combination therapy • Heterogeneity • Lung Cancer • Non Small Cell Lung Cancer • Solid Tumor • AGK • BRAF • EML4 • KIAA1549 • MAP2K1 • NRAS • TRIM24