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GIST

(P 197) DIFFERENTIAL EFFECTS OF ANAGRELIDE IN GASTROINTESTINAL STROMAL TUMORS (GIST) IN VITRO

    Author(s)

  • Manikandan Murugesan, Ph.D (he/him/his)

    Post Doctoral Fellow
    Dept. of Surgery, Moores Cancer Center, University of California San Diego
    San DIego, California, United States

    • Co-Author(s)

  • Merel van Dijk (she/her/hers)

    Medical Student
    Radboud University Medical Center
    Nijmegen, Gelderland, Netherlands

  • MA

    Mark Antkowiak, MD

    Post Doctoral Fellow
    Dept. of Surgery, Moores Cancer Center, University of California San Diego
    San Diego, California, United States

  • CT

    Chih-Min Tang, Ph.D

    Staff Research Associate-3
    Dept. of Surgery, Moores Cancer Center, University of California San Diego
    San DIego, California, United States

  • Shashwath Kalladi Malli, PhD (he/him/his)

    Post Doctoral Fellow
    Dept. of Surgery, Moores Cancer Center, University of California San Diego
    San Diego, California, United States

  • Adrian Sanchez-Fdez, Ph.D

    Post Doctoral Fellow
    Dept. of Surgery, Moores Cancer Center, University of California San Diego
    San DIego, California, United States

  • TD

    Terence M. Doherty, n/a

    Senior Science Writer
    Dept. of Surgery, Moores Cancer Center, University of California San Diego
    San Diego, California, United States

  • MD

    Margo Dona, Ph.D

    Assistant Professor
    Institute of Biology Leiden, Leiden University
    Leiden, Zuid-Holland, Netherlands

  • Diwakar Guragain, Ph.D (he/him/his)

    Assistant Project Scientist
    Dept. of Surgery, Moores Cancer Center, University of California San Diego
    San Diego, California, United States

  • HS

    Harri Sihto, Ph.D

    Adjunct Professor
    Dept. of Pathology, University of Helsinki and Helsinki University Hospital
    Helsinki, Uusimaa, Finland

  • Jason K. Sicklick, M.D., FACS (he/him/his)

    Professor/Principal Investigator
    Dept. of Surgery, Moores Cancer Center, University of California San Diego
    San Diego, California, United States

Objective: GISTs are molecularly heterogeneous tumors that include KIT-mutant and succinate dehydrogenase deficient (SDH-def) subtypes. Unlike KIT-mutant GIST, SDH-def GIST are somewhat resistant to standard tyrosine kinase inhibitors. Phosphodiesterase 3A (PDE3) was previously identified as highly expressed in GIST, and together with its binding partner, Schlafen family member 12 (SLFN12), have been implicated in drug-induced apoptosis in GIST. This study evaluated PDE3A and SLFN12 expression, as well as the anti-tumor effects of the PDE3 inhibitor, anagrelide in KIT-mutant vs. SDH-def GIST in vitro models.

Methods: Models included KIT-mutant (GIST882: KIT K642E; GIST-T1: KIT V560_Y579del) and SDH-def [SD-437A (SDHA 1432_1432+1delGG); SD-435C (SDHC R133*)]. Expression of PDE3A and SLFN12 were analyzed in cell lines using bulk transcriptomics and expression was analyzed in 27 GIST using single-nucleus RNA-seq (snRNAseq). Cells treated with anagrelide were analyzed for drug sensitivity, mRNA/protein expression, apoptosis induction, and migration/invasion capacity.

Results: Bulk and snRNAseq revealed higher PDE3A expression in KIT-mutant tumor cells, while SLFN12 was low across these subtypes. Relative to GIST882, PDE3A protein was highly expressed in GIST-T1 (10.8-fold) followed by SD-437A (3.1-fold) and SD-435C (1.3-fold) cells. In contrast, SLFN12 was highly expressed in GIST882, but had < 50% expression (p < 0.01) in other lines. In GIST882, anagrelide induced cytotoxicity (IC₅₀ 20 nM), with caspase-3 activation and PARP cleavage. However, SDH-def and GIST-T1 cells were resistant to anagrelide (IC₅₀ >50 µM) induced apoptosis. However, at sub-lethal doses (GIST882: 2 nM; GIST-T1: 2 µM; SD-437A/SD-435C: 3 µM), anagrelide significantly reduced migration/invasion in GIST-T1, SD-437A, and SD-435C cells by 30–45% vs. GIST882 ( < 10%), p < 0.05.

Conclusion: Anagrelide shows context-dependent activity in GIST, with apoptosis induced in PDE3A(Low)-SLFN12(High) GIST882 cells, while exerting anti-migratory and anti-invasive effects in PDE3A(High)-SLFN12(Low) SDH-def and GIST-T1 cells despite lack of apoptosis. These findings support further exploration of PDE3A and SFLN12 signaling as a potential target for distinct GIST subtypes.