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Hisashi Harada

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    P2.13 - Targeted Therapy (Not CME Accredited Session) (ID 962)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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      P2.13-35 - Inhibition of H3K27 Demethylation is Toxic in Poorly Differentiated Small Cell Lung Cancer (ID 13288)

      16:45 - 18:00  |  Author(s): Hisashi Harada

      • Abstract


      Small cell lung cancer (SCLC) is a solid tumor with a 5% 5-year survival rate, and often contain major alterations within the epigenetic landscape. In a high throughput drug screen by the Genomics of Drug Sensitivity in Cancer (GDSC), SCLC cell lines were found exquisitely sensitive to GSK-J4, a selective H3K27 demethylase inhibitor. Given that increases in H3K27me3 are associated with cell differentiation, GSK-J4 offers a potential therapeutic strategy in the treatment of SCLC. Our goals here were to validate the screen data, determine the mechanism of GSK-J4 action, and identify putative biomarkers that impart sensitivity to this epigenetic therapeutic strategy.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Using a combination of bioinformatics and western blotting, we identified biomarkers for the effectiveness of GSK-J4 in SCLC. RNA-seq, western blotting, cell viability and apoptosis assays were used to determine the mechanism for GSK-J4 action. Multiple mouse patient derived xenograft (PDX) models were used to determine the effectiveness of GSK-J4 in vivo.

      4c3880bb027f159e801041b1021e88e8 Result

      We found that several markers of neuroendocrine differentiation were markedly decreased in GSK-J4 sensitive SCLCs when compared to resistant SCLC cell lines, suggesting that a lack of differentiation imparts SCLC sensitivity to GSK-J4. As expected, GSK-J4 induced a global accumulation of H3K27me3 in SCLC cell lines, and induced cell death through an ER stress mediated pathway. This cell-death response was blocked by knockdown of the ER stress pathway. Further, mouse SCLC PDX models demonstrated that GSK-J4 is effective in poorly differentiated SCLC in vivo.

      8eea62084ca7e541d918e823422bd82e Conclusion

      These findings offer a novel epigenetic-based therapeutic strategy for the treatment of poorly differentiated SCLCs.