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X. Yang

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    MINI 16 - EGFR Mutant Lung Cancer 2 (ID 130)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 1
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      MINI16.12 - Lung Adenocarcinoma Transformation into Small-Cell Lung Cancer after Treatment: Clinical Evidence and the Exploratory Mechanism (ID 2485)

      16:45 - 18:15  |  Author(s): X. Yang

      • Abstract
      • Presentation
      • Slides

      The phenomenon of small cell lung cancer(SCLC) transformation in EGFR mutated adenocarcinoma had been previously identified as a resistant mechanism. However, this phenomenon was only reported in single case and a repeat biopsy patient cohort. Moreover, the underlying molecular mechanism remains unclear. Previous study found that the inactivation of TP53 and Rb1 could efficiently transform neuroendocrine and alveolar type 2 cells into SCLC. We inferred that TP53 and Rb1 might also play an important role in SCLC transformation. So we use the sh-RNA mediated depletion of RB1 adenocarcinoma cell line, that also have TP53 inactivation in nature, to investigate the molecular mechanism of SCLC transformation.

      Both primary and metastatic tissue were analyzed on 3 SCLC transformation patients by whole genome sequencing (WGS). We knock down RB1 in TP53 inactivation cell lines, PC-9, HCC-827 and H1975. Western blot and immunohistochemistry (IHC) were used to confirm RB1 knock down and expression of neuroendocrine (NE) markers. Trans well cell invasion assay and softer agar clone formation test were investigated the change of invasion and migration. CCK8 kit was used to evaluate relative viability of cells after RB1 knock down. Cell cycle and apoptosis were determined by folw cytometry. And we use balb/c mice for cell line tumorgenesis.

      ① Pathological analysis of the 3 patients’ primary lesion and the consistent EGFR mutation status confirmed the phenomenon of SCLC transformation. WGS showed the copy number variation of primary tumor and transformed metastasis was distinct. RB1 is lost in 100% of the three transformed cases but occur in one patient’s primary tissue in extremely low frequency(<5%). ② PC-9, HCC827 and H1975 cell line showed up-regulation of NE markers after sh-RNA mediated RB1 depletion, which presented more capable of invasion and migration. Cell folw cytometry showed more cells was in G2 and S phase after RB1 knock down. The expression of Bik and puma that belong to Bcl-2 family was up-regulated after RB1 inactivation compared with the control group.

      The NE differentiation and changes in invasion, migration, apoptosis and cell cycle indicated that the loss of TP53 and RB1 promote the process of SCLC transformation. TP53 and RB1 deficiency may be a necessary event for SCLC transformation to emerge, but is still insufficient to induce SCLC transformation.

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