Author of

• 34687

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  MA01 - Novel Systemic Treatment in NSCLC (ID 102)

  • Event: WCLC 2020
  • Type: Mini Oral
  • Track: Antibody Drug Conjugates, Novel Therapeutics and Cytotoxics
  • Presentations: 1
  • Moderators:
  • Coordinates: 1/29/2021, 11:45 - 12:45, Scientific Program Auditorium

  • 34694

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    MA01.10 - MDM2 Inhibitor APG-115 Suppresses Cell Proliferation and Tumor Growth in Preclinical Models Of NSCLC Harboring STK11 Mutations (ID 1438)

    11:45 - 12:45  |  Presenting Author(s): Hao Sun
    • Abstract
    • Presentation
    • Slides

    Introduction
    

    Liver kinase B1 (LKB1/STK11) is one of the most frequent mutated genes in non-small-cell lung cancer (NSCLC). Patients harboring STK11 mutations proven resistant to immunotherapy and lacking of effective therapies. A published genomic database indicates MDM2 inhibition is effective in NSCLC cells carrying STK11 mutations. Currently in clinical development, APG-115 is a novel, orally active small-molecule mouse double minute 2 homolog (MDM2) inhibitor. APG-115 potently activates P53 pathway and induces apoptosis in TP53 wild-type tumors.

    Methods
    

    We first investigated the effect of APG-115 on cell proliferation in a panel of human TP53 wild-type NSCLC cell lines with (i.e., A549, H460, H1944, H1666) or without (i.e., H226, H292) STK11 mutations. Next, a panel of 10 TP53 wild-type patient-derived xenograft (PDX) models of NSCLC with or without STK11 mutations were used to validate in vitroresults. Lastly, we investigated the involvement of ferroptosis to explore the mechanisms of action of APG-115.

    Results
    

    APG-115 more effectively inhibited cell growth in STK11-mutant cell lines in vitro, giving rise to the half maximal inhibitory concentration (IC50) values ranging from 0.15 to 0.38 μM in comparison with 0.18 to 1.8 μM in wild-type cell lines. In vivo, oral administration of APG-115 (100 mg/kg) daily for 14 days led to substantial tumor growth inhibition in 3 out of 10 PDX models (30%). Among these 3 models, two harbored STK11 mutations. Furthermore, the response rate in PDXs harboring mutant STK11 is higher than the wildtype group (66% vs 14%).The above results indicate that STK11mutations may further enrich the responders to APG-115 therapy. Considering that the disorder in AMP-activated protein kinase (AMPK) pathway sensitizes cancer cells to ferroptosis-mediated cell deaths, we further unveiled that, in comparison with the wild-type cell lines, STK11-mutant cell lines showed significantly increased lipid peroxidation level after APG-115 intervention, suggesting that the effect of APG-115 is mediated by ferroptosis.

    

    Conclusion
    

    APG-115 is more effective in inhibiting cell proliferation and tumor growth in STK11-mutant NSCLC cells and xenograft models, respectively, in comparison with the wild-type counterparts. Further, antitumor activity of APG-115 in STK11-mutant tumors may be mediated through ferroptosis. Taken together, our data warrant clinical investigation of APG-115 in treating NSCLC tumors with STK11 mutations.

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