PLX4720 / Daiichi Sankyo - LARVOL DELTA

A bioinformatics-driven approach to identify biomarkers and elucidate the pathogenesis of type 2 diabetes concurrent with pulmonary tuberculosis. (PubMed, Sci Rep) - "Seven drugs (ERK_440_1713, JAK_8517_1739, Palbociclib_1054, PLX.4720_1036, Savolitinib_1936, Selumetinib_1736, and VX.11e_2096) exhibited significant sensitivity in patients with high-expression or low-expression of C1QA. Five genes (C1QA, MMP8, MMP9, CD248, and LINC00278) have potential as diagnostic markers for PTB + T2DM, and three genes (C1QA, MMP8, and MMP9) were upregulated in the peripheral blood of PTB + T2DM patients. Our findings may serve as a valuable reference for future research and clinical applications."

Biomarker • Journal • Diabetes • Infectious Disease • Metabolic Disorders • Pulmonary Disease • Respiratory Diseases • Tuberculosis • Type 2 Diabetes Mellitus • C1QA • CEACAM8 • COL1A2 • IL17A • MAPK4 • MIR25 • MIR363 • MIR671 • MIR942 • MMP8 • MMP9

Understanding how treatment responses alter the myeloid compartment in BRAF-mutant melanoma (IMMUNOLOGY 2025) - "To investigate this, we employed a tamoxifen-inducible engrafted skin model of melanoma driven by BRAFV600E expression and Pten loss (Braf/Pten model)...We now show that the addition of the synthetic triterpenoid CDDO-Me to the BRAFi PLX4720 arrested resistance and significantly reduced tumor burden...Consistent with this, we identified alterations in myeloid cell recruitment and subset activation during the development of BRAFi resistance using scRNA-seq and flow cytometry. Collectively, these findings indicate that CDDO-Me may impede the development of BRAFi resistance and support its role in novel combination therapies for melanoma.Keywords: Animals Human Rodent; Cells Monocytes/Macrophages; Molecules Cell Surface Molecules; Tissues Skin"

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

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

Dissecting Branch-Specific Unfolded Protein Response Activation in Drug-Tolerant BRAF-Mutant Melanoma using Data-Independent Acquisition Mass Spectrometry. (PubMed, bioRxiv) - "These targets were subsequently applied to investigate proteomic changes in multiple patient-derived BRAF-mutant melanoma cell lines treated with a BRAF inhibitor (PLX4720, i.e., vemurafenib). Our findings revealed differential regulation of the XBP1s branch of the UPR in the BRAF-mutant melanoma cell lines after PLX4720 treatment, likely due to calcium activation, suggesting that the UPR plays a role as a non-genetic mechanism of drug tolerance in melanoma. In conclusion, the validated branch-specific UPR proteomic targets identified in this study provide a robust framework for investigating this pathway across different cell types, drug treatments, and disease conditions in a high-throughput manner."

Journal • CNS Disorders • Diabetes • Melanoma • Metabolic Disorders • Oncology • Solid Tumor • ATF6 • BRAF • ERN1

The Role of Coagulation-Related Genes in Glioblastoma: A Comprehensive Analysis of the Tumor Microenvironment, Prognosis, and Treatment. (PubMed, Biochem Genet) - "The CRG-based risk signature model effectively predicts the prognosis of GBM patients and aids in assessing the efficacy of ICI therapy and chemotherapy. Furthermore, the genes LEFTY2, SERPINC1 and the drug PLX4720 offer potential directions for the development of novel therapeutic strategies for GBM."

Biomarker • IO biomarker • Journal • Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Infectious Disease • Oncology • Solid Tumor • MMP2 • SPP1

Subtype cluster analysis unveiled the correlation between m6A- and cuproptosis-related lncRNAs and the prognosis, immune microenvironment, and treatment sensitivity of esophageal cancer. (PubMed, Front Immunol) - "Furthermore, nine candidate drugs with potential therapeutic efficacy in EC were identified: Bleomycin, Cisplatin, Cyclopamine, PLX4720, Erlotinib, Gefitinib, RO.3306, XMD8.85, and WH.4.023. Furthermore, it identifies potential therapeutic agents with efficacy against EC. These findings hold significant promise for enhancing the survival of EC patients and provide valuable insights to inform clinical decision-making in the management of this disease."

Biomarker • IO biomarker • Journal • Esophageal Cancer • Oncology • CD40 • CD40LG • ELF3 • HHLA2 • HNF1A • LGALS9 • MIR181A1 • TNFRSF14 • TNFRSF18 • TNFSF15

Genome-wide transcriptome analysis and drug target discovery reveal key genes and pathways in thyroid cancer metastasis. (PubMed, Front Endocrinol (Lausanne)) - "Application of aspirin, a TXA2 inhibitor, significantly reduced lung metastases...Braf-mutant Met cells developed resistance to BRAFV600E inhibitor PLX4720, but remained sensitive to β-catenin inhibitor PKF118-310. We have identified several overexpressed genes/pathways in thyroid cancer metastasis, making them attractive therapeutic targets. Given the complexity of metastasis involving multiple pathways (PD-L1, Mertk, IL6, COX-1/Tbxas1-TXA2), simultaneously targeting more than one of these pathways may be warranted to achieve better therapeutic effect for metastatic thyroid cancer."

IO biomarker • Journal • Endocrine Cancer • Oncology • Solid Tumor • Thyroid Gland Anaplastic Carcinoma • Thyroid Gland Carcinoma • Thyroid Gland Follicular Carcinoma • Thyroid Gland Papillary Carcinoma • AXL • CCL11 • CCL2 • CTNNB1 • CXCL5 • IL5 • IL6 • MERTK

Combinatorial Targeting of Common Docking and ATP Binding Sites on Mps1 MAPK for Management of Pathogenic Fungi. (PubMed, J Agric Food Chem) - "In vivo assays demonstrated that TAK-733 exhibits combinational effects with ATP-competitive inhibitors PLX-4720 and A378-0. Collectively, we present TAK-733 as having a new mechanism of action suitable for combinational application with ATP-competitive inhibitors in the management of pathogenic fungi."

Journal • MAP2K1

A Novel Mitochondrial-Related Gene Signature for the Prediction of Prognosis and Therapeutic Efficacy in Lower-Grade Glioma. (PubMed, Biochem Genet) - "Finally, using data from the CTRPv2 and GDSC2 datasets to assess chemotherapy response in LGG, it was predicted that the chemotherapeutic agents AZD6482, MG-132, and PLX-4720 might be potential agents for patients in the high-MiAS group of LGG. In contrast, overexpression of OCIAD2 enhanced these abilities of glioma cells. This study found that MRGs were correlated with LGG patient prognosis, which is expected to provide new treatment strategies for LGG patients with different MiAS."

Gene Signature • IO biomarker • Journal • Brain Cancer • CNS Tumor • Glioma • Oncology • Solid Tumor

Involvement of ICAM5 in Carcinostasis Effects on LUAD Based on the ROS1-Related Prognostic Model. (PubMed, J Inflamm Res) - "PLX4720 may be a suitable treatment for the high-risk patient population...Personalized therapy may play an essential role in treatment. We further investigated the role of ICAM5 in inhibiting the malignant bioactivity of LUAD cells."

IO biomarker • Journal • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ICAM5 • ROS1

BrafV600E-induced cancer inflammation in a mouse model of thyroid tumorigenesis (ESMO 2024) - "To investigate reversibility of the inflammatory response to BrafCA/+ activation, mutant mice aged 6 months were fed with Braf kinase inhibitor Vemurafenib (PLX4720) or control dietary pellets for 4 weeks. All cytokines showed a gradual increase of gene expression between age 1 to 6 months in non-induced mutant mice, and a subsequent decrease at 12 months. Inflammatory response due to Braf activation is an early event in thyroid carcinoma development, with a time-course dependent expression pattern. Targeted Braf inhibition significantly down-regulates cytokine expression."

IO biomarker • Preclinical • Endocrine Cancer • Oncology • Solid Tumor • Thyroid Gland Carcinoma • IL1B • IL6 • TNFA

CTHRC1 is associated with BRAF(V600E) mutation and correlates with prognosis, immune cell infiltration, and drug resistance in colon cancer, thyroid cancer, and melanoma. (PubMed, Biomol Biomed) - "Additionally, a high level of CTHRC1 was correlated with decreased sensitivity to antitumor drugs (vemurafenib, PLX-4720, dabrafenib, and SB-590885) targeting the BRAF(V600E) mutation. This study provides evidence of a significant correlation between CTHRC1 and the BRAF(V600E) mutation, suggesting its potential utility as a diagnostic and prognostic biomarker in human colon cancer, thyroid cancer, and melanoma."

Immune cell • IO biomarker • Journal • Colon Cancer • Colorectal Cancer • Endocrine Cancer • Gastrointestinal Cancer • Melanoma • Oncology • Solid Tumor • Thyroid Gland Carcinoma • BRAF

The ERK5 pathway in BRAFV600E melanoma cells plays a role in development of acquired resistance to dabrafenib but not vemurafenib. (PubMed, FEBS Lett) - "We investigated the role of the ERK5 pathway in BRAFV600E melanoma cells and cells with acquired resistance to PLX4720 (vemurafenib) and dabrafenib. However, in dabrafenib-resistant cells, ERK5 inhibition reduced viability and enhanced the anti-proliferative effect of MEK1/2 inhibition. Targeting the ERK5 pathway may represent a therapeutic opportunity in dabrafenib-resistant melanoma."

Journal • Preclinical • Genetic Disorders • Melanoma • Oncology • Skin Cancer • Solid Tumor

Analysis of correlation between high expression of nucleoporin 85 (NUP85) and immune cell infiltration in hepatocellular carcinoma (PubMed, Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi) - "The expression of NUP85 was significantly correlated with multiple drugs, such as Milademetan (PD0325901), a structural analog of Vemurafenib (PLX4720), and Regorafenib (PD0325901). These factors significantly and unfavorably affected the OS of HCC patients, and the areas under the ROC curve (AUC) for the 1-year, 3-year, and 5-year OS prognostic diagnosis of HCC patients were all greater than 0.7. Conclusion The high expression of NUP85 in HCC is correlated with a poor prognosis and is related to various immune cells and drugs, making it a potential biomarker for di-agnosis, treatment, and prognosis in HCC."

Immune cell • Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor

Targeting NG2 relieves the resistance of BRAF-mutant thyroid cancer cells to BRAF inhibitors. (PubMed, Cell Mol Life Sci) - "Based on this finding, we propose and demonstrate an alternative strategy for targeting NG2 to effectively treat BRAF-mutant thyroid cancers by combining multiple kinase inhibitor (MKI) Sorafenib or Lenvatinib with PLX4720. Thus, this study uncovers a new mechanism in which NG2 contributes to the resistance of BRAF-mutant thyroid cancer cells to BRAF inhibitor, and provides a promising therapeutic option for BRAF-mutant thyroid cancers."

Journal • Endocrine Cancer • Oncology • Solid Tumor • Thyroid Gland Carcinoma • CSPG4

EXTRA-NUCLEAR TERT COUNTERACTS OXIDATIVE STRESS AND PROMOTES PROGRESSION IN PAPILLARY THYROID CARCINOMA. (PubMed, Transl Res) - "We demonstrated that TERT is exported from the nucleus in response to OS induced either from H2O2 or the BRAF inhibitor PLX4720...In conclusion, our data indicate that extra-nuclear TERT is involved in reducing the effect of excessive OS, thus promoting cancer cell survival. Extra-nuclear TERT may thus represent a marker of cancer progression and a possible therapeutic target in PTC."

Journal • Endocrine Cancer • Oncology • Solid Tumor • Thyroid Gland Carcinoma • Thyroid Gland Papillary Carcinoma • CDKN1A

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

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

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

Complement and coagulation cascades are associated with prognosis and the immune microenvironment of lower-grade glioma. (PubMed, Transl Cancer Res) - "By means of oncoPredict, MG-132, BMS-536924, PLX-4720, and AZD6482 were identified as potential sensitive drugs for high-risk patients, of which MG-132 was particularly recommended for high-risk patients. We performed in vitro experiments to explore the anti-glioma effect of MG-132, and the results demonstrated MG-132 could inhibit the proliferation and migration of glioma cells. Our findings show that CCC genes are associated with the prognosis and immune infiltration of LGG and provide possible immunotherapeutic and novel chemotherapeutic strategies for patients with LGG based on the risk signature."

IO biomarker • Journal • Brain Cancer • CNS Tumor • Glioma • Oncology • Solid Tumor • SERPINA1

TRAF2 decrease promotes the TGF-β-mTORC1 signal in MAFLD-HCC through enhancing AXIN1-mediated Smad7 degradation. (PubMed, FASEB J) - "We proved the signal of the mechanistic target of rapamycin complex 1 (mTORC1) could be activated in the presence of TGF-β, and was enhanced in TRAF2-/- cells...We also discovered that PLX-4720 could bind with AXIN1 and restrained the tumor proliferation of TRAF2-/- in mice fed with high-fat diet (HFD). Our findings indicate that TRAF2 plays a significant role in the pathogenesis of MAFLD-HCC. The reduction of TRAF2 expression leads to the enhancement of the TGF-β-mTORC1 pathway by facilitating AXIN1-mediated Smad7 degradation."

Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Liver Cancer • Metabolic Dysfunction-Associated Steatotic Liver Disease • Oncology • Solid Tumor • Targeted Protein Degradation • AXIN1 • SMAD7 • SMURF2 • TGFB1 • TNFA

Combination BRAFV600E inhibition with the multitargeting tyrosine kinase inhibitor axitinib shows additive anticancer activity in BRAFV600E-mutant anaplastic thyroid cancer. (PubMed, Thyroid) - "The novel combination of axitinib and BRAFV600E inhibition enhanced anticancer activity in in vitro and in vivo models of BRAFV600E-mutant ATC. This combination may have clinical utility in BRAFV600E-mutant ATC that is refractory to current standard therapy, namely combined BRAF and MEK inhibition."

Journal • Endocrine Cancer • Oncology • Solid Tumor • Thyroid Gland Anaplastic Carcinoma • Thyroid Gland Carcinoma • AURKB • JUN

GENOME‐WIDE TRANSCRIPTOME ANALYSIS REVEALS KEY GENES AND PATHWAYS ASSOCIATED WITH THYROID CANCER METASTASIS (ATA 2023) - "BVE-Met cells developed resistance to BRAFV600E inhibitor PLX4720, but remained sensitive to β-catenin/KDM4A inhibitor PKF118-310. In summary, we have identified several targetable genes/pathways in thyroid cancer metastasis. Given the complexity of metastatic cells in evasion of host immune response, simultaneously targeting more than one of these pathways (PDL1, Mertk, IL6, COX-1/Tbxas1-TXA2) may be warranted to achieve better therapeutic effect."

IO biomarker • Endocrine Cancer • Oncology • Solid Tumor • Thyroid Gland Anaplastic Carcinoma • Thyroid Gland Carcinoma • Thyroid Gland Follicular Carcinoma • Thyroid Gland Papillary Carcinoma • AXL • CCL11 • CCL2 • CD24 • CD44 • CDKN2A • CTNNB1 • CXCL5 • IL5 • IL6 • KRAS • MERTK • MET • PD-1 • TP53

Machine learning-driven exploration of drug therapies for triple-negative breast cancer treatment. (PubMed, Front Mol Biosci) - "It was observed that Panobinostat, PLX4720, Lapatinib, Nilotinib, Selumetinib, and Tanespimycin were six effective drugs against the TNBC cell lines. Furthermore, we did not find any radioresistance markers for the TNBC. The proposed biomarkers and drug sensitivity analysis will provide potential candidates for future clinical investigation."

Journal • Machine learning • Breast Cancer • Hormone Receptor Breast Cancer • Inflammatory Arthritis • Oncology • Solid Tumor • Triple Negative Breast Cancer • ER • HER-2 • PGR • SETD7

SPI1-mediated MIR222HG transcription promotes proneural-to-mesenchymal transition of glioma stem cells and immunosuppressive polarization of macrophages. (PubMed, Theranostics) - " This study demonstrates that targeting SPI1 to block transcription of the MIR222HG cluster helps to reduce radioresistance and combat the immunosuppressive microenvironment in GBM. PLX-4720 is a potential GBM drug and radiosensitizer."

Journal • Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Oncology • Solid Tumor • HDAC5 • MIR21 • MIR221 • MIR222 • SOCS3 • SPI1