Abstract 1813P
Background
Osimertinib (Osi), a 3rd generation EGFR-TKI, has shown great efficacy in advanced NSCLC patients (pts) with EGFR sensitizing mutations and EGFR T790M resistance mutation, but the acquisition of resistance is inevitable and the treatment regimen is limited. As an oral multi-targeted tyrosine kinase inhibitor, anlotinib effectively inhibits tumor growth and angiogenesis. We found that anlotinib plus Osi showed favorable efficacy in a subset of Osi-resistant NSCLC pts in clinical practice. However, the underlying mechanism remains unclear. Therefore, we focused on elucidating the potential mechanism of anlotinib plus Osi in overcoming acquired resistance to Osi.
Methods
EGFR T790M mutation was expressed in the H1975 cell line, but not in the HCC827 cell line. Two cell lines, H1975 Osi-resistant (OR) cell line and HCC827 Osi-resistant (OR) cell line, were established via stepwise-dose escalation. Cell viability assay, clone formation assay and cell scratch test were preformed to examine the effects of anlotinib or Osi or the combination on the two OR cell lines. Combination Index (CI) of anlotinib plus Osi on the two OR cell lines was calculated to evaluate the synergistic effect. Quantitative real-time PCR (qRT-PCR) and Western blot analysis were used to detect the levels of EGFR/FGFR/Akt/Erk to explore the potential mechanism.
Results
Based on qRT-PCR and Western blot analysis, FGFR1 and FGFR2 were overexpressed in the HCC827 OR cell line and H1975 OR cell line, respectively. The IC50 values of anlotinib for both the two OR cell lines were significantly lower than their parental cell lines. Compared with anlotinib or Osi alone, the combination more strongly inhibited the proliferation and migration of the two OR cell lines. CI values demonstrated the synergistic effect of anlotinib plus Osi. Western blot analysis showed the combination effectively inhibited the phosphorylation of both EGFR and FGFR, then down-regulate the phosphorylation levels of Akt/Erk.
Conclusions
FGFR overexpression may be the mechanism of acquired resistance to Osi. Anlotinib plus Osi could overcome this resistance via inhibiting EGFR and FGFR signaling pathways, which provides a novel treatment option for Osi-resistant NSCLC.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.