Reference Detail

Contact

Missing content? – Request curation!

Request curation for specific Genes, variants, or PubMed publications.

Have questions, comments or suggestions? - Let us know!

Email us at : ckbsupport@jax.org

Ref Type Journal Article
PMID (29997151)
Authors Pishas KI, Drenberg CD, Taslim C, Theisen ER, Johnson KM, Saund RS, Pop IL, Crompton BD, Lawlor ER, Tirode F, Mora J, Delattre O, Beckerle MC, Callen DF, Sharma S, Lessnick SL
Title Therapeutic Targeting of KDM1A/LSD1 in Ewing Sarcoma with SP-2509 Engages the Endoplasmic Reticulum Stress Response.
Journal Molecular cancer therapeutics
Vol 17
Issue 9
Date 2018 09
URL
Abstract Text Multi-agent chemotherapeutic regimes remain the cornerstone treatment for Ewing sarcoma, the second most common bone malignancy diagnosed in pediatric and young adolescent populations. We have reached a therapeutic ceiling with conventional cytotoxic agents, highlighting the need to adopt novel approaches that specifically target the drivers of Ewing sarcoma oncogenesis. As KDM1A/lysine-specific demethylase 1 (LSD1) is highly expressed in Ewing sarcoma cell lines and tumors, with elevated expression levels associated with worse overall survival (P = 0.033), this study has examined biomarkers of sensitivity and mechanisms of cytotoxicity to targeted KDM1A inhibition using SP-2509 (reversible KDM1A inhibitor). We report, that innate resistance to SP-2509 was not observed in our Ewing sarcoma cell line cohort (n = 17; IC50 range, 81 -1,593 nmol/L), in contrast resistance to the next-generation KDM1A irreversible inhibitor GSK-LSD1 was observed across multiple cell lines (IC50 > 300 μmol/L). Although TP53/STAG2/CDKN2A status and basal KDM1A mRNA and protein levels did not correlate with SP-2509 response, induction of KDM1B following SP-2509 treatment was strongly associated with SP-2509 hypersensitivity. We show that the transcriptional profile driven by SP-2509 strongly mirrors KDM1A genetic depletion. Mechanistically, RNA-seq analysis revealed that SP-2509 imparts robust apoptosis through engagement of the endoplasmic reticulum stress pathway. In addition, ETS1/HIST1H2BM were specifically induced/repressed, respectively following SP-2509 treatment only in our hypersensitive cell lines. Together, our findings provide key insights into the mechanisms of SP-2509 cytotoxicity as well as biomarkers that can be used to predict KDM1A inhibitor sensitivity in Ewing sarcoma. Mol Cancer Ther; 17(9); 1902-16. ©2018 AACR.

Filtering

  • Case insensitive filtering will display rows where any text in any cell matches the filter term
  • Simple literal full or partial string matches
  • Separate multiple filter terms with a spaces, order doesn't matter (a b c and c b a are equivalent )
  • Filtering will only apply to rows that are already loaded on the page, filtering has no impact on query parameters
  • Use quotes to match a longer phrase which contains spaces "mtor c1483f"

Sorting

  • Generally, the default sort order for tables is set to be first column ascending, however, specific tables may set a different default sort order.
  • Click on any column header arrows to sort by that column
  • Hold down the Shift key and click multiple columns to sort by more than one column, be sure to set ascending or descending order for a given column, before moving on to the next column.

Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
GSK-LSD1 KDM1A Inhibitor 12 GSK-LSD1 is an irreversible KDM1A inhibitor that covalently binds to the FAD pocket and blocks enzymatic activity of KDM1A, thereby potentially inhibiting cell viability and tumor growth (PMID: 29997151, PMID: 26175415).
SP-2509 SP2509|HCI2509|HCI-2509 KDM1A Inhibitor 12 SP-2509 is a small molecule that selectively inhibits KDM1A, which potentially results in increased apoptosis and inhibition of colony formation, cell viability, and tumor growth (PMID: 29997151, PMID: 24699304, PMID: 24963049).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown Ewing sarcoma not applicable SP-2509 Preclinical - Cell culture Actionable In a preclinical study, EWS fusion-positive Ewing sarcoma cell lines demonstrated reduced viability following SP-2509 treatment that correlated with induction of KDM1B expression post-treatment in culture (PMID: 29997151). 29997151
Unknown unknown Ewing sarcoma no benefit GSK-LSD1 Preclinical - Cell culture Actionable In a preclinical study, Ewing sarcoma cell lines did not demonstrate sensitivity to GSK-LSD1 in culture (PMID: 29997151). 29997151
Unknown unknown Ewing sarcoma no benefit Tranylcypromine Preclinical - Cell culture Actionable In a preclinical study, Ewing sarcoma cell lines did not demonstrate sensitivity to Parnate (tranylcypromine) in culture (PMID: 29997151). 29997151
Unknown unknown rhabdomyosarcoma not applicable SP-2509 Preclinical - Cell culture Actionable In a preclinical study, SP-2509 treatment inhibited viability of rhabdomyosarcoma cell lines in culture (PMID: 29997151). 29997151
Unknown unknown osteosarcoma not applicable SP-2509 Preclinical - Cell culture Actionable In a preclinical study, SP-2509 treatment inhibited viability of osteosarcoma cell lines in culture (PMID: 29997151). 29997151