Tango Therapeutics, Inc. · NASDAQ:TNGX
Tango Therapeutics — Technical Presentation (2021)
9 slides from Tango Therapeutics's technical presentation, 2021
Slide 1: VRK1 is a Novel Synthetic Lethal Target in VRK2-methylated Glioblastoma
VRK1 is a Novel Synthetic Lethal Target in VRK2-methylated Glioblastoma Julie Shields, Samuel R. Meier, Justin Engel, Madhavi Bandi, Maria L. Dam Ferdinez, Wenhai Zhang, Shan-chuan Zhao, Minjie Zhang, Ashley Choi, Yi Yu, Xuewen Pan, Brian McMillan, Brett Williams, Robert Tjin Tham Sjin, Douglas Whit
Slide 2: VRK1 emerges as a novel synthetic lethal target in TANDEM
VRK1 emerges as a novel synthetic lethal target in TANDEM, Tango’s proprietary cancer dependency map TANDEM Targets Bimodality Coefficient CRISPR Score Differential Note: Genes are color-coded by tractability
Slide 3: VRK2-methylated glioblastoma and neuroblastoma cell lines are sensitive to VRK1 loss
VRK2-methylated glioblastoma and neuroblastoma cell lines are sensitive to VRK1 loss CCLE cell line data TCGA tumor data Low grade glioma Glioblastoma 1.0 0.8 VRK2 Methylation 0.6 0.4 0.2 0.0 0 2 4 VRK2 Expression • ~ 60% of brain tumors have low VRK2 expression due to aberrant promoter methylation
Slide 4: VRK1 is a mitotic kinase with roles in transcription factor regulation and DNA damage response
VRK1 is a mitotic kinase with roles in transcription factor regulation and DNA damage response VRK1 substrates VRK2 substrates Nuclear Envelope Formation Monslave et al, 2018 Campillo-Marcos et al, 2018 Campillo-Marcos et al, 2021 VRK1 and VRK2 are paralogs with some overlapping roles
Slide 5: VRK1 is synthetic lethal with VRK2, and the lethality is dependent on VRK1 kinase activity
VRK1 is synthetic lethal with VRK2, and the lethality is dependent on VRK1 kinase activity VRK1 knockdown in HAP1 isogenic cell line pair Rescue experiments in HAP1 VRK2null cell line K71M - kinase dead mutant K178E - kinase inactive mutant
Slide 6: VRK2-methylated glioblastoma cell lines are sensitive to VRK1 knockdown in vitro and in vivo
VRK2-methylated glioblastoma cell lines are sensitive to VRK1 knockdown in vitro and in vivo VRK1 1.0 ** VRK2 Colony Forming knockdown 0.8 unmethylated Fraction in GBM cell 0.6 VRK2 methylated line panel 0.4 (in vitro) 0.2 0.0 U251MG VRK2 low U251MG VRK2 high VRK1 VRK2 VRK2 Tumor volume (mm3) 2000 S
Slide 7: Accumulation of proteins and phospho-proteins involved in G2/M arrest and DNA repair pathways
Accumulation of proteins and phospho-proteins involved in G2/M arrest and DNA repair pathways Total Proteomics Phospho Proteomics VRK2 low vs VRK2 high VRK2 low vs VRK2 high -LOG10(q-value) -LOG10(q-value) LOG Fold Change LOG Fold Change
Slide 8: Summary
Summary ▪ VRK1 is synthetic lethal in VRK2-methylated glioblastoma and VRK1 kinase activity is necessary for the synthetic lethal interaction ▪ VRK1 knockdown in a VRK2-methylated glioblastoma cell line results in G2/M arrest and subsequent DNA damage ▪ These results suggest that inhibiting VRK1 kin
Slide 9: Acknowledgements
Acknowledgements • Tango Therapeutics: • Contract research partners: Scientific teams at ChemPartner, Pharmaron and IQProteomics • Cleveland Clinic: Erin Mulkearns-Hubert, Kelly Mitchell and Justin Lathia • Broad Institute: Maria “Masha” Alimova Contact information • Tango Therapeutics: info@tangotx