Author of

• 18973

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  P2.01 - Advanced NSCLC (ID 618)

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

  • 24633

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    P2.01-075c - FGFR1 as an Intrinsic Resistance Mechanism in Erlotinib Treated EGFR Mutated NSCLC (ID 9344)

    09:00 - 09:00  |  Author(s): J. Vad-Nielsen
    • Abstract

    Background:
    A major obstacle of NSCLC targeted treatment is the occurrence of resistance. Drug inhibiting the Epidermal Growth Factor Receptor (EGFR) has been a treatment for more than a decade and is given as first line treatment in EGFR mutated patients. However, up to 30 % of the patients with EGFR mutations experience no objective response to EGFR-TKIs and hence appear as intrinsic resistant. We and others have discovered, that increased FGFR1 expression occurs in the lung adenocarcinoma cell lines with acquired resistance to EGFR inhibitors, but no studies have investigated high FGFR1 expression as an intrinsic resistance mechanism to erlotinib.
    
    Method:
    CRISPR-Cas9 SAM was used for genetically upregulation of FGFR1 in the adenocarcinoma cell lines HCC827 and PC9. Proliferation and response to erlotinib was investigated with CellTiter 96® AQueous Non-Radioactive Cell Proliferation Assay (Promega). Protein expression and was investigated using western blotting. FGF2 levels was investigated in serum samples from 36 EGFR-mutated patients using the Quantikine HS ELISA kit for Human FGF basic Immunoassay (R&D) and FGFR1 expression will be investigated with IHC in a cohort of 30 EGFR mutated patients.
    
    Result:
    FGFR1 upregulation in PC9 and HCC827 (FGFR1+) did not by itself decrease the sensitivity to erlotinib. However, when the cells were treated with the FGFR1 ligand FGF2 the cells became significantly (p<0.05) more resistant compared to control cells. FGF2 in itself also made the control cells less sensitive to erlotinib, hence we hypothesized that serum levels of FGF2 may influence the response to erlotinib in EGFR mutated patients. FGF2 ELISA performed on 36 EGFR mutated patients, however, revealed that serum-FGF2 did not correlate with PFS. At this moment, we are conducting WB analysis of the FGFR1 pathway for FGFR1+ cells and control cells treated with FGF2 and erlotinib to reveal the functional bypass signalling. We are also preparing IHC for FGFR1 on tissue from EGFR mutated patients obtained prior to erlotinib treatment to confirm our in vitro findings.
    
    Conclusion:
    FGFR1 overexpression is a putative intrinsic resistance mechanism to erlotinib treatment. FGF2 levels may influence the activity and resistance mediation by FGFR1, but serum levels of FGF2 are not determining for erlotinib response in EGFR mutated patients.