^
    8ms
    EZH2 suppresses ferroptosis in hepatocellular carcinoma and reduces sorafenib sensitivity through epigenetic regulation of TFR2. (PubMed, Cancer Sci)
    In conclusion, our study illustrates how EZH2 epigenetically regulates TFR2 expression through H3K27 me3, thereby suppressing ferroptosis. The combination of the tazemetostat with sorafenib exhibits superior synergistic effects in anticancer therapy and sensitizes the HepG2-SR cells to sorafenib, shedding new light on delaying and ameliorating sorafenib resistance.
    Journal
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    EZH2 (Enhancer of zeste 2 polycomb repressive complex 2 subunit)
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    EZH2 overexpression • EZH2 amplification
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    sorafenib • Tazverik (tazemetostat)
    almost2years
    Use of comprehensive molecular profiling to identify additional clinically-relevant alterations compared to targeted gene panels (AACR 2023)
    Genetic and expression alterations identified by the BostonGene Tumor PortraitTM TestEvent type analyzed in targeted panelsEvent typeCohort (N patients)*% cohort with event or # biomarkersEvents, status, or subtypeYesSNV/IndelMG (21)10%FAT4 Y558_V590delinsCAfs*5 LOF mutation COL2A1 W1348Nfs*13 LOF mutationYesSNV/IndelMD (40)6%KMT2B R1779* LOF mutation KMT2C S143Vfs*3 LOF mutation PRKDC Y4046* LOF mutationYesGermlineMG (21)5%MUTYH rs36053993, germline, pathogenicYesGermlineMD (40)3%BTD rs13078881, germline, pathogenicYesCNAMG (21)43%IGF1R amplification +8 copies MGMT loss FANCA loss MCL1 amplification +10 copies MYOCD amplification +3 copies AKT2 amplification +8 copies AMACR amplification +6 copies YAP1 amplification +7 copies TRAF2 loss EZH2 amplification +2 copies HMGA2 amplification +100 copies FRS2 amplification +61 copies DDIT3 amplification +39 copiesYesCNAMD (40)27.5%ERK1 amplification +2 copies FOXO1 amplification +5 copies HMGA2 amplification +2, +8 copies KMT2C amplification +3 copies NCOR1 amplification +7 copies TERT amplification +6 copies TSPAN31 amplification +30 copies HSF1 lossYesFusionsMG (20)10%MDM2-CR1 MDM2-TXNDC12 AC090825.1-IGF1RYesFusionsMD (39)15%FUS-KIAA1549 KIAA1549-CREB3L2 HMGA2-LRRC37A3 NAB2-STAT6 PPP1R12A-PAWR RB1-ZAR1LNoTMB**MG+MD (61)8%35.67 mut/Mb (Desmoid fibromatosis) 8.48 mut/Mb (Cutaneous angiosarcoma) 8.9 mut/Mb (Sarcoma, NOS) 16.1 mut/Mb (Skin Angiosarcoma) 18.8 mut/Mb (Undifferentiated pleomorphic sarcoma)NoMSI statusMG+MD (61)100%StableNoHLA loss of heterozygosityMG+MD (61)11%HLA-I LOH (Leiomyosarcoma (N=1), Ewing Sarcoma (N=1)) HLA-A (Dedifferentiated liposarcoma (N=1)) HLA-I (Chondrosarcoma (N=3), High-grade sarcoma (N=1))NoTargetable surface molecule overexpressionMG+MD (59)81%CTLA4, EGFR, ERBB2, MAGEA3, PD1, PDL1, TIM3, TROP, ERBB2, FOLR1, NECTIN4, ROR1, TROP2NoMolecular Functional PortraitTM typeMG+MD (59)32%FibroticNoMolecular Functional PortraitTM typeMG+MD (59)17%Immune DesertNoMolecular Functional PortraitTM typeMG+MD (59)24%Immune-Enriched, FibroticNoMolecular Functional PortraitTM typeMG+MD (59)27%Immune-Enriched, Non-fibroticNoMHC deficiencyMG+MD (59)3%MHC class I/II deficiencyNoMHC deficiencyMG+MD (59)3%MHC class II deficiencyNoFDA label biomarkersMG+MD (59)7 biomarkers- Desmoid fibromatosis, TMB 35.67 mut/Mb (Pembrolizumab) - Angiosarcoma, TMB 16.1 mut/Mb (Pembrolizumab); - Undifferentiated pleomorphic sarcoma, MSI, TMB 18.8 mut/Mb (Pembrolizumab); - Cutaneous angiosarcoma, PALB2 pathogenic germline variant (Olaparib); - Chondrosarcoma IDH1 R132L (Ivosidenib)NoTranscriptomic biomarkersMG+MD (59)29 biomarkersCD8+ T cell number; PDL1 expression level; SLFN11 expression level; SMARCB1 expression; CD8+ T cell numberNoDiagnostic biomarkersMG+MD (59)9 biomarkersNAB2-STAT6; MXI1-NUTM1; EWSR1-NR4A3; EWSR1-FLI1; EWSR1-CREB3L1; NAB2-STAT6----*RNA analysis failed for 2 patients. Therefore, any expression based analysis was performed on n=20 and n=39 for the MG and MD cohort, respectively. **Tumor mutational burden is considered high for FFPE samples when TMB>8mut/Mb.
    Clinical • Tumor mutational burden • PARP Biomarker • PD(L)-1 Biomarker • IO biomarker
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    EGFR (Epidermal growth factor receptor) • HER-2 (Human epidermal growth factor receptor 2) • PD-L1 (Programmed death ligand 1) • TMB (Tumor Mutational Burden) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • RB1 (RB Transcriptional Corepressor 1) • CD8 (cluster of differentiation 8) • PD-1 (Programmed cell death 1) • MCL1 (Myeloid cell leukemia 1) • FOLR1 ( Folate receptor alpha ) • PALB2 (Partner and localizer of BRCA2) • KMT2C (Lysine Methyltransferase 2C) • ROR1 (Receptor Tyrosine Kinase Like Orphan Receptor 1) • SLFN11 (Schlafen Family Member 11) • CTLA4 (Cytotoxic T-Lymphocyte Associated Protein 4) • IGF1R (Insulin-like growth factor 1 receptor) • SMARCB1 (SWI/SNF Related, Matrix Associated, Actin Dependent Regulator Of Chromatin, Subfamily B, Member 1) • KIAA1549 • EWSR1 (EWS RNA Binding Protein 1) • FANCA (FA Complementation Group A) • HAVCR2 (Hepatitis A Virus Cellular Receptor 2) • YAP1 (Yes associated protein 1) • NECTIN4 (Nectin Cell Adhesion Molecule 4) • NR4A3 (Nuclear receptor subfamily 4 group A member 3) • NCOR1 (Nuclear Receptor Corepressor 1) • AKT2 (V-akt murine thymoma viral oncogene homolog 2) • FAT4 (FAT Atypical Cadherin 4) • FLI1 (Fli-1 Proto-Oncogene ETS Transcription Factor) • FRS2 (Fibroblast Growth Factor Receptor Substrate 2) • FUS (FUS RNA Binding Protein) • MUTYH (MutY homolog) • HMGA2 (High mobility group AT-hook 2) • KMT2B (Lysine Methyltransferase 2B) • STAT6 (Signal transducer and activator of transcription 6) • CREB3L1 (CAMP Responsive Element Binding Protein 3 Like 1) • DDIT3 (DNA-damage-inducible transcript 3) • MAGEA3 (MAGE Family Member A3) • MXI1 (MAX Interactor 1) • NUTM1 (NUT Midline Carcinoma Family Member 1) • PRKDC (Protein Kinase, DNA-Activated, Catalytic Subunit) • COL2A1 (Collagen Type II Alpha 1 Chain) • HSF1 (Heat Shock Transcription Factor 1) • NAB2 (NGFI-A Binding Protein 2)
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    PD-L1 expression • TMB-H • HER-2 overexpression • SLFN11 expression • KMT2C mutation • FANCA mutation • IDH1 R132 • MCL1 amplification • CTLA4 expression • KMT2B mutation • TERT amplification • AKT2 amplification • CTLA4 underexpression • EZH2 amplification • FRS2 amplification • IGF1R amplification
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    Keytruda (pembrolizumab) • Lynparza (olaparib) • Tibsovo (ivosidenib)