Author of

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  FP12 - Tumor Biology and Systems Biology - Basic and Translational Science (ID 188)

  • Event: WCLC 2020
  • Type: Posters (Featured)
  • Track: Tumor Biology and Systems Biology - Basic and Translational Science
  • Presentations: 1
  • Moderators:
  • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall

  • 35734

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    FP12.10 - IGF-1R Inhibition in Small Cell Lung Cancer: Role of Brigatinib (ID 1953)

    00:00 - 00:00  |  Author(s): Naveen Kumar Perumal
    • Abstract
    • Presentation
    • Slides

    Introduction
    

    Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine tumor characterized by early distant spread and chemoresistance. The overall 5-year survival rate has remained a dismal 7% over the last 25 years, and systemic treatment options for patients with relapsed SCLC have remained unchanged. Even though patients often initially respond to chemotherapy, they routinely relapse. Relapsed SCLC is often chemorefractory, resulting in poor survival. Brigatinib (AP26113) is a selective anaplastic lymphoma kinase-positive (ALK) inhibitor; however, besides ALK inhibition, brigatinib inhibits IGF-1R signaling. IGF-1R is thought to be a key target in SCLC. The objective of this project is to identify the mechanism and therapeutic efficacy of brigatinib along with currently available chemotherapeutic drugs in SCLC.

    Methods
    

    We used various SCLC cell lines and normal human bronchial epithelial cells (NHBE) for the screening of IGF-1R by quantitative real-time PCR and western blotting. MTT assays were performed to identify the inhibitory role of brigatinib on IGF-1R positive and negative SCLC cells. We have also performed apoptosis and cell cycle experiments to identify the effect of brigatinib on apoptosis and cell growth, respectively. Further, we have formed CRISPR-Cas9 based IGF-1R, and IGF-1 knockout. These isogenic cells were used to identify the chemoresistance mechanisms.

    Results
    

    We chose five SCLC cell lines based on IGF-1R level (SBC-5 ^high, H82^high, H526^basal, SBC-3 ^basal and H69^basal). The IC₅₀ of brigatinib ranged from 50 nM to 100 nM in H526 and H69 cells lines and from 750 nM to 1 µM in SBC-3, SBC-5, and H82 cell lines. IGF-1R knockdown SCLC cells showed enhanced sensitivity to cisplatin and etoposide, as compared to control clone cells. We observed that combination of brigatinib and etoposide increased apoptosis. SBC-3 and SBC-5 cells ware treated with brigatinib alone, etoposide alone and combination of brigatinib and etoposide. The percentage of apoptotic cells was significantly higher in cells treated with combination etoposide and brigatinib (SBC-3 - 54.1 %; SBC-5 - 37.5%) compared to brigatinib alone (12.9%; 37.8%), etoposide alone (31.2%; 14.9%) and untreated controls (3.7%; 8.1%).

    Conclusion
    

    Brigatinib induced IGF-1R inhibition may have therapeutic implications in SCLC. Targeting IGF-1R signaling and identifying possible mechanisms of IGF-1R mediated chemoresistance in SCLC can potentially reduce the SCLC associated mortality. Clinical trials of brigatinib in patients with SCLC and high IGF-1R expression are warranted.

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