PLX4720 / Daiichi Sankyo - LARVOL DELTA

Antitumor effects of CEP32496 on urothelial carcinoma with BRAF mutation (V595E) in dogs. (PubMed, Can J Vet Res) - "For reference, 7 BRAF inhibitors, including GDC0879, PLX4720, encorafenib, vemurafenib, dabrafenib, AZ628, and RAF265, were also evaluated. In the xenograft model, 10 mg/kg body weight of CEP32496 resulted in a significant decrease (P < 0.05) in tumor growth in mice, with severe and extensive necrosis on histopathological examination. These results suggested that CEP32496 exerts antitumor effects on both cell proliferation and tumor growth in UC with V595E."

Journal • Oncology • Solid Tumor • Urothelial Cancer • BRAF

HeyL, a Notch downstream target, is upregulated in BRAFV600E-driven papillary thyroid cancer (EACR 2026) - "We investigated whether HeyL is regulated by BRAFV600E and whether its expression links developmental programmes to thyroid tumorigenesis.Material and Material and Tumorigenesis was induced in TgCreERT2; BrafCA/+ mice by tamoxifen administration...To determine kinase dependency, BRAFV600E-positive mice were treated with the selective BRAF inhibitor PLX4720, and HeyL expression was compared to untreated controls... HeyL is significantly upregulated in BRAFV600E-driven PTC in a MAPK-dependent manner. These findings support functional crosstalk between MAPK and Notch signaling pathways in thyroid carcinogenesis and suggest that developmental regulators such as HeyL may be reactivated during tumor progression. HeyL may represent a potential biomarker and therapeutic target in BRAFV600E-positive thyroid cancer."

Oncology • Solid Tumor • Thyroid Gland Carcinoma • Thyroid Gland Papillary Carcinoma

Global Geo-Pharmacogenomics: Environmental Mutational Signatures Drive Population-Level Heterogeneity in Anticancer Drug Response. (PubMed, J Xenobiot) - "First, a linear regression-based pharmacogenomic screen across four datasets (GDSC1, GDSC2, CTRP, CCLE; 1001 cell lines, 31 cancer types) identified 608 statistically significant (p < 0.01) mutational signature-drug interactions, revealing that UV-associated signature SBS7a is associated with broad-spectrum therapeutic resistance, including to BRAF inhibitors (PLX-4720, p < 10-4), while pollution-driven oxidative stress (SBS18) is associated with sensitivity to p38 MAPK inhibition (VX-702, r = -0.45, p < 10-9)...These findings suggest that a patient's environmental exposure history may constitute a measurable pharmacogenomic variable. This exploratory framework warrants validation in independent datasets and with individual-level geographic data before clinical application."

Biomarker • Heterogeneity • Journal • Inflammatory Arthritis • Oncology

Therapy-induced senescence promotes immune remodeling and tumor aggressiveness in BRAF-inhibitor–resistant melanoma (SID 2026) - "However, combination treatment with the PLX4720 and the senolytic drug ABT-263 improved control of resistant tumors and partially normalized the TIME by restraining excessive T-cell proliferation, increasing the proportion of effector and TCF-1+ stem-like CD8+ T cells, dendritic cells, and reducing neutrophil infiltration. Together, our findings suggest that targeting TIS and its associated secretory programs may limit progression of BRAFi-resistant melanoma through positive modulation of antitumor immunity."

Melanoma • Oncology • Solid Tumor • CD8

A RHO GTPase pathway signature as a potential prognostic biomarker and therapeutic target in bladder cancer (AACR 2026) - "Bioinformatic drug-prediction analysis identified PI-103 and PLX-4720 as potential therapeutic compounds for the high-risk group. This study establishes a robust prognostic model for BLCA based on RHO GTPase cycle effector genes and highlights UACA, CLTC, and SNAP23 as potential prognostic biomarkers and promising therapeutic targets. Our findings provide a foundation for further investigation into RHO GTPase pathway effectors and their potential role in improving BLCA diagnosis and treatment."

Biomarker • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • CLTC

Treatment Responses Alter Myeloid Activation in BRAF-Mutant Melanoma (IMMUNOLOGY 2026) - "We have shown that the addition of the synthetic triterpenoid CDDO-Me to the BRAFi PLX4720 arrested resistance and significantly reduced tumor burden, while CDDO-Me as a single agent or in combination with BRAFi prior to resistance was ineffective. The iTME changes with tumor progression and responds dynamically to BRAFi treatment and resistance. This work establishes for the first time that BRAFi promotes myeloid-mediated induction of T cell activation, which is lost at resistance but can be rescued with the addition of CDDO-Me. Because BRAFi resistance and iTME immunosuppression is reversed by CDDO-Me treatment, these results provide the foundation for its potential use in combination therapies for melanoma."

Genetic Disorders • Melanoma • Skin Cancer • Solid Tumor • BRAF • PTEN

Novel targets for BRAFV600E and BRAFV600ERAC1P29S drug resistant melanoma (AACR 2024) - "Rac1 P29S -transfected and PLX4720 resistant cell lines had an increase in the Mek/Erk signaling pathway...Drugs that target different subunits of the eIF4F complex (CR-1-31-B, Ribavirin and Briciclib) also decrease BRAFV600E/RAC1P29S and the DR melanoma cell lines growth specifically...When tested in a syngraft model, CR-1-31-B and rapamycin reduced tumor size when using YUMM1.7, YUMM1.7- RAC1P29S and YUMM1.7 RAC1P29S-DR cell lines. Next, we sought to investigate the effect of inhibiting mTOR and eiF4F in the PD-1/PD-L1 axis in tumor cells and tumor associated dendritic cells and macrophages, and how targeting these modifies the tumor microenvironment."

IO biomarker • Melanoma • Oncology • Solid Tumor • BRD4 • CDK9 • EIF4A1 • EIF4E • EIF4G1 • MYC • RAC1 • SMAD3

Paradoxical activation of kinases occurs directly with ATP-competitive kinase inhibitors and is observable biochemically at physiologically relevant drug concentrations (AACR 2024) - "Previous work by other investigators (at Genentech and the Rosen lab, MSKCC) demonstrated that PLX4720 (precursor to Vemurafenib) paradoxically activated wild type BRAF, but not BRAF mutants, by driving dimerization of the kinase in drug concentrations insufficient to inhibit both members of the dimerized pair. Such paradoxical activation could be driving both toxicities and inefficacy against cancers expressing some of these activatable kinases. This information could suggest novel opportunities for combination therapy and improve outcomes by contraindicating certain medication from use based on tumor expression profile."

Oncology • BRAF • KIT

Drug-centric prior improves drug response signature identification in partially overlapping, large-scale pharmacogenomic datasets (AACR 2024) - "We evaluate our performance in three ways: 1) we test if the joint model improves the prioritization of known consensus biomarkers for the drugs shared between the two cohorts; 2) we test if the joint model improves the recapitulation of shared drug mechanism of action as compared to the single dataset models; 3) we evaluate the joint models with respect to pathway enrichment as compared to the single dataset models. We evaluated the performance of our joint model for 5 drugs shared between the 2 resources: selumetinib, tanespimycin, nutlin 3A, mirdametinib and PLX4720. We present an application of a Bayesian group factor analysis model, where we employ a drug-centric prior to transfer information about drugs screened in multiple datasets. We show that joint models leveraging partially overlapping large-scale pharmacogenomic datasets from the Broad and Sanger institutes can overall improve drug signature identification."

Biomarker • Genomic data • Oncology

Targeting TGFBR2 neddylation suppresses metastatic/immunosuppressive abilities and enhances responsiveness to BRAF inhibitor in melanoma with BRAF V600E mutation (AACR 2025) - "This study explores whether targeting TGFBR2 neddylation suppresses metastasis/immunosuppression and enhances BRAF inhibitor response. Gene Set Enrichment Analysis (GSEA) was performed to predict the possible pathways suppressed by the treatment with the protein neddylation inhibitor MLN4924 in melanoma cells. Our data suggest that targeting TGFBR2 neddylation might be a novel strategy to combat the metastatic/immunosuppressive and BRAF inhibitor-resistant melanoma with BRAF V600E mutation."

Metastases • Melanoma • Oncology • Solid Tumor • NEDD8 • TGFB1 • TGFBR2

Non-Canonical Neddylation of TGFBR2 as a Therapeutic Target in BRAF-Mutant Melanoma (AAD 2026) - " GSEA data indicated that MLN4924 treatment significantly suppressed key oncogenic pathways, including TGF-β signaling and epithelial-mesenchymal transition (EMT). Functionally, TGFBR2 knockdown reduced migration and immunosuppressive abilities in highly metastatic cell lines, while its overexpression promoted these malignant phenotypes and increased resistance to the BRAF inhibitor PLX4720... Our findings demonstrate that the non-canonical neddylation of TGFBR2 is a critical mechanism driving therapeutic resistance, metastasis, and immunosuppression in BRAF V600E melanoma. Targeting this specific neddylation-TGFBR2 axis offers a promising novel strategy to improve treatment outcomes."

Melanoma • Solid Tumor • BRAF • TGFBR2

Prognostic integration of tumor microenvironment and parthanatos-related genes in gastric cancer: a machine learning-driven risk model and immune landscape profiling. (PubMed, Front Immunol) - "High-risk patients had immunosuppressive TME and poor immunotherapy response, with Imatinib/PLX4720 showing potential efficacy. CD36/KIT overexpression promoted GC malignancy; their inhibition remodeled TME cytokines and, for the first time, activated the PA pathway to induce GC cell death."

Biomarker • IO biomarker • Journal • Gastric Cancer • Oncology • Solid Tumor • AIF1 • AKAP12 • CD14 • CD36 • EGF • IFNG • IL10 • SCARB1 • TNFA

Targeting Melanoma-Associated Fibroblasts to Overcome Cancer Stem Cell-Driven Drug Resistance. (PubMed, J Am Coll Surg) - "Activating Notch1 signaling in melanoma-associated fibroblasts overcomes BRAF inhibitor resistance by disrupting cancer stem cell niches. This stromal-targeted approach represents a novel therapeutic strategy to complement surgical and systemic therapies in melanoma patients with drug-resistant disease."

Journal • Melanoma • Oncology • Solid Tumor • CAFs • NGFR • NOTCH1

Disulfidptosis-related genes signature predicts prognosis and immune microenvironment in colon cancer. (PubMed, Front Mol Biosci) - "As a risk factor, RAB7A relating to poor prognosis was identified in our study, and was a potential target for therapeutic agents such as PLX4720 and PD-0325901, while OXSM was the opposite. The 5-DRGs prognostic model can be used to assess the prognosis of patients with CC, and reflect the characteristics of their immune microenvironment. With RAB7A and OXSM as key determinants, this model provides a clinically applicable framework for risk stratification and personalized treatment guidance."

IO biomarker • Journal • Tumor mutational burden • Colon Cancer • Colorectal Cancer • Inflammatory Arthritis • Oncology • Solid Tumor • CTLA4 • NCAM1 • RAB7A • SLC7A11 • TMB

A Cuproptosis-Related lncRNA Signature Predicts Prognosis and Shapes the Immune Landscape in Primary Lower-Grade Glioma. (PubMed, Genet Res (Camb)) - "Several prospective drugs targeting samples with high scores were predicted, namely, MG-132, PLX-4720, AZD6482, and BMS-536924. Moreover, experiments conducted in vitro demonstrated that knockdown of the expression of the CRLs TPRG1-AS1 and LYRM4-AS1 might impair the migration and proliferation capacity of glioma cells. Taken together, these results indicate that CRLs are linked to prognosis and immune characteristics in LGG and give innovative therapeutic methods for individuals with LGG across different risk stratifications."

Biomarker • IO biomarker • Journal • Brain Cancer • Glioma • Oncology • Solid Tumor • TP63

A migrasome-related LncRNA signatures for predicting prognosis and immunotherapeutic response in colorectal cancer. (PubMed, Sci Rep) - "In addition, drug sensitivity screening revealed that high-risk patients were more likely to resist current targeted drugs including PLX-4720 and JAK-8517 than low-risk patients. This study identifies a novel migrasome-related lncRNA signature as a reliable prognostic tool for CRC, highlighting its potential in patient stratification and personalized therapy."

IO biomarker • Journal • Colorectal Cancer • Oncology • Solid Tumor

BRAF inhibition increases TGFβ2 production and stimulates metastasis in mice with endogenous BRAFV600E-induced hepatocellular carcinoma. (PubMed, Proc Natl Acad Sci U S A) - "While the BRAF inhibitor PLX4720 effectively reduced primary tumors and extended survival, it paradoxically increased sarcomatoid metastases...We conclude that BRAFV600E drives diverse primary tumors but only one type of metastasis and that RAF inhibition, while effective against primary tumors, may promote metastasis through TGFβ2-mediated EMT. Although RAF inhibitors remain promising therapies, their unintended role in enhancing metastasis raises concerns that may extend beyond liver cancer to other BRAFV600E-driven malignancies."

Journal • Preclinical • Hepatocellular Cancer • Hepatology • Liver Cancer • Melanoma • Oncology • Sarcoma • Solid Tumor • CDKN2A • TGFB1 • TGFB2 • TP53

Identification and validation of prognostic genes associated with m6A-regulated programmed cell death in acute lymphoblastic leukemia. (PubMed, Sci Rep) - "Sensitivity analysis of 60 chemotherapy agents indicated that Bicalutamide was more effective in LRG, while ATRA, CCT018159, PHA-665752, and PLX4720 demonstrated greater efficacy in HRG. RT-qPCR validation confirmed upregulation of CDK4 and downregulation of CFLAR in ALL samples (P < 0.05). This study offers important theoretical support for the prognostic evaluation and personalized treatment strategies in ALL."

Biomarker • Journal • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • CDK4 • CFLAR

scGSDR: Harnessing gene semantics for single-cell pharmacological profiling. (PubMed, Commun Biol) - "Literature review of top-ranking genes in predictions such as BCL2, CCND1, and PIK3CA for PLX4720 confirmed their relevance. Overall, scGSDR, by incorporating gene semantics, enhances predictive modeling of cellular responses to diverse drugs, proving invaluable for scenarios involving both single drug and combination therapies and effectively identifying key resistance-related pathways, thus advancing precision medicine and targeted therapy development."

Journal • BCL2 • CCND1 • PIK3CA

Gadd45B Deficiency Drives Radio-Resistance in BRAFV600E-Mutated Differentiated Thyroid Cancer by Disrupting Iodine Metabolic Genes. (PubMed, Cancers (Basel)) - "Gadd45B plays a pivotal role in regulating the differentiation status and RAI sensitivity of BRAFV600E-mutated thyroid cancer. These findings identify Gadd45B as a promising therapeutic target for restoring RAI responsiveness in RAIR-DTC patients."

Journal • Oncology • Solid Tumor • Thyroid Gland Carcinoma • GADD45B • MYC

Characterization and inhibitor sensitivity of ARAF, BRAF, and CRAF kinases. (PubMed, J Biol Chem) - "Type I inhibitor SB590885 is roughly equipotent across RAF isoforms and, as expected, type I.5 inhibitors are typically most potent against BRAFV600E. Crystal structures of CRAF in complex with type I.5 inhibitor PLX4720 reveal an asymmetric CRAF dimer with one CRAF subunit bound in the inactive state and the second bound in an αC-helix-in, active conformation with an altered inhibitor pose. Our findings have important implications for understanding the pharmacology of current RAF inhibitors and will inform development of new agents with distinct isoform selectivity."

Journal • Melanoma • Oncology • Solid Tumor • Thyroid Gland Carcinoma • Thyroid Gland Papillary Carcinoma • ARAF • BRAF

TRP-related gene signatures predict survival and the immune microenvironment in rectal cancer: a comprehensive bioinformatics study. (PubMed, Front Immunol) - "Furthermore, several targeted drugs, including MK-2206, pazopanib, JNK inhibitor VIII, PLX4720, and NU-7441, were associated with risk scores. This study identified five TRP-related biomarkers associated with RC prognosis, providing novel insights into the role of TRP channels in RC development. These findings may contribute to a deeper understanding of RC pathogenesis and offer potential targets for personalized therapy."

Biomarker • Gene Signature • Journal • Colorectal Cancer • Oncology • Rectal Cancer • Solid Tumor • CD8 • GLTP

Characterization and inhibitor sensitivity of ARAF, BRAF, and CRAF complexes. (PubMed, bioRxiv) - "Type I inhibitor SB590885 is roughly equipotent across RAF isoforms and, as expected, type I.5 inhibitors are typically most potent against BRAFV600E. Crystal structures of CRAF in complex with type I.5 inhibitor PLX4720 reveal an asymmetric CRAF dimer with one CRAF subunit bound in the inactive state and the second bound in an aC-helix-in, active conformation with an altered inhibitor pose. Our findings have important implications for understanding the pharmacology of current RAF inhibitors and will inform development of new agents with distinct isoform selectivity."

Journal • Melanoma • Oncology • Solid Tumor • Thyroid Gland Carcinoma • Thyroid Gland Papillary Carcinoma • ARAF • BRAF

Identification of anoikis-related genes to develop a risk model and predict the prognosis and tumor microenvironment in rectal adenocarcinoma. (PubMed, Front Genet) - "Drug sensitivity analysis revealed differences in the IC50 values of OSI-027, PLX-4720, UMI-77, and Sapitinib between the high-risk and low-risk groups. Enrichment analysis revealed that these prognostic ARGs were primarily enriched in pathways and biological processes related to tumorigenesis. The risk model of ARGs can effectively predict READ prognosis and provide potential therapeutic targets."

Biomarker • Journal • Colorectal Adenocarcinoma • Colorectal Cancer • Oncology • Rectal Adenocarcinoma • Solid Tumor • ALDH1A1 • BRCA1 • KRT17

Anti-tumor efficacy of RAF/MEK inhibitor VS6766 in KRAS-mutated colorectal cancer cells. (PubMed, Cancer Chemother Pharmacol) - "Taken together, this study provides the first experimental evidence to demonstrate that all G12 mutation cell lines are sensitive to VS6766 applied either alone or combined with 5-FU or AKT inhibitor."

Journal • Colorectal Cancer • Oncology • Solid Tumor • KRAS