Virtual Library

Start Your Search

C. Yang



Author of

  • +

    P1.01 - Advanced NSCLC (ID 757)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Advanced NSCLC
    • Presentations: 1
    • +

      P1.01-077 - Oncogenic Potential of a Novel HER2 755PL In-Frame (HER2PL) Mutation in Lung Adenocarcinoma (ID 10139)

      09:30 - 16:00  |  Author(s): C. Yang

      • Abstract

      Background:
      Never smoking Asian patients with lung adenocarcinoma are usually accompanied with recurrent occurring mutations of oncogenic drivers, such as EGFR, HER2, ALK fusions, ROS1 fusions etc. HER2 mutations were identified in approximately 2–4% of NSCLCs and these mutations were usually mutually exclusive with other driver mutations. Preclinical studies have suggested that overexpression of HER2 or mutations of the HER2 kinase domain are critical in oncogenic transformation and tumorigenesis. We found a novel HER2 755[PL] in-frame (also called HER2[PL]) mutation in a 52-year old never smoking lung adenocarcinoma patient. She did not have EGFR mutation. Patient was treated with a second generation of EGFR tyrosine kinase inhibitor (TKI), afatinib and had responded. However, the role of HER2[PL] mutation in lung tumorigenesis and its response to EGFR TKIs have never been addressed before.

      Method:
      We established a plasmid construct carrying a HER2 gene with HER2[PL] and transfected into normal murine fibroblasts, NIH/3T3 and human lung adenocarcinoma, NCI-H358 which express wide type EGFR. HER2 activation pathways were examined by western blots of phosphorylation of down-stream molecules with and without gefitinib and afatinib treatment.

      Result:
      Overexpression of HER2[PL] mutation can activate HER signaling pathways in both NIH/3T3 and NCI-H358. HER2[PL] mutation induces much higher phosphorylation of HER2 and downstream AKT signaling pathway compared to wide-type HER2. In addition, we found that HER2PL mutation can trigger HER2 signaling in ligand-independent manner and afatinib can significantly decrease HER2[PL] mutation-induced HER2 signaling pathway compared to a first generation of EGFR TKI, gefitinib. Furthermore, we found that the distribution of HER2[PL] mutation is in cytosol as well as on the membrane and the expression of p-HER2 (Tyr1221/1222) can be effectively attenuated with afatinib treatment in NCI-H358 stable lines using immunofluorescence assay. The cell growth and drug sensitivity to different generations of EGFR TKI in NCI-H358 lines transfected with HER2[PL] mutation are under investigation.

      Conclusion:
      This research may bring us new insights to understand the oncogenic significance of HER2[PL] mutation and be applied to relevant therapeutics.