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Lizhong Zeng



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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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      P2.13-37 - Chloroquine overcomes acquired resistance to icotinib in vitro and in vivo through STAT3/STMN1 pathway (ID 13689)

      16:45 - 18:00  |  Author(s): Lizhong Zeng

      • Abstract
      • Slides

      Background

      Icotinib, an oral first-generation EGFR inhibitor, in non-small cell lung cancer (NSCLC) patients rarely results in complete tumor remission and frequently challenged by acquired resistance, eventually leading to tumor relapse. Recently, autophagy is considered as an important mechanism of resistance to TKI. Herein, we investigated the autophagy induction as well as the effects of its inhibitor chloroquine on anti-acquired resistant lung adenocarcinoma activity of icotinib in vitro and in vivo.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Apoptosis was measured with flow cytometry and tunel. Growth-inhibitory effects of icotinib were evaluated in vitro with MTT and colony formation assay as well as in vivo with mouse xenograft models. Autophagy was performed by transmission electron microscopy, immunochemistry and immunofluorescence. The inhibition of autophagy was achieved with siRNA or inhibitors. Gene expression was determined by western blot.

      4c3880bb027f159e801041b1021e88e8 Result

      Icotinib potently induced apoptosis in PC-9 cell. Significant pro-apoptotic effects were noted in vitro and in vivo. In contrast, PC-9/GR and H1975 were found to be highly resistant to icotinib treatment. Autophagy was found in patients with acquired resistance to EGFR-TKIs and Icotinib was also detected to induce productive autophagy in PC-9/GR and H1975 cells. Mechanistically, icotinib triggers STAT3/STMN1-dependent early protective autophagic response in PC-9/GR and H1975 cells. The crucial role of this pathway in icotinib-induced drug resistance was verified by silencing STAT3 and STMN1. Genetic and pharmacological autophagy blockade resulted in significant icotinib-induced apoptosis in cells defined as sensitive or resistant. Finally, chlororquine-based combinatorial therapy effectively blocked tumor growth in xenografts with TKI-resistant cancer cells.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our findings strongly support chloroquine, generally considered nontoxic and remarkably inexpensive, might be used in combination with TKIs in patients with non–small cell lung cancer, harboring EGFR mutations to overcome TKI resistance and prolong survival.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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