Author of

• 20179

  +

  P2.15 - SCLC/Neuroendocrine Tumors (ID 716)

  • Event: WCLC 2017
  • Type: Poster Session with Presenters Present
  • Track: SCLC/Neuroendocrine Tumors
  • Presentations: 1
  • Moderators:
  • Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)

  • 23525

    +

    P2.15-010 - Etk Interacting with PFKFB4 Modulates Chemoresistance of Small Cell Lung Cancer by Regulating Autophagy (ID 9023)

    09:30 - 09:30  |  Author(s): J. Zhang
    • Abstract

    Background:
    Epithelial and endothelial tyrosine kinase(Etk), also known as Bone marrow X kinase (Bmx), was found to be critical in modulating chemoresistance of small cell lung cancer(SCLC) in our preliminary study. However, the molecular mechanisms of Etk leading to chemoresistance in SCLC remain obscure.
    
    Method:
    Knockdown of Etk by siRNAs was performed to evaluate autophagy change in SCLC. Subsequently, a microarray analysis identified PFKFB4 as a downstream molecule of Etk, and CoIP and GST-pull down was used to test protein interaction. We then explored whether PFKFB4 affected autophagy of SCLC. Gain or loss-of-function in vitro or in vivo was used to evaluate the effects PFKFB4 on chemotherapy sensitivity. The expression of PFKFB4 in SCLC tissues were measured by immunohistochemistry(IHC). Besides, luciferase assays, Western blot and CCK8 assay were performed to confirmed whether miR-218 regulates Etk and its effect on chemoresistance. As Etk shares conserved domains with Btk(Bruton’s tyrosine kinase) family, we also explored whether ibrutinib, a Btk inhibitor used in leukemia, affected chemotherapy sensitivity of SCLC.
    
    Result:
    Etk affected autophagy in SCLC, and directly inhibition of autophagy sensitized cells to chemotherapy. PFKFB4 was found as a downstream molecule of Etk and they interacted with each other in protein level directly. Moreover, knockdown of PFKFB4 suppressed autophagy of SCLC. PFKFB4 affected chemoresistance of SCLC in vitro and in vivo, and high level of PFKFB4 was associated with poor therapeutic response and prognosis. Furthermore, miR-218 directly modulated Etk expression as a novel regulator and it affected chemoresistance in SCLC. We demonstrated that ibrutinib exhibited a synergistic effect with chemotherapy in SCLC.
    
    Conclusion:
    Figure 1 Our results demonstrated for the first time that Etk interacts with PFKFB4 to modulate the chemoresistance of SCLC by autophagy and Etk is a direct target of miR-218. These genes may be predictive factors for the chemotherapy response as well as potential therapeutic targets in SCLC.