Abstract 225P
Background
Third-generation EGFR-TKI is the mainstay for advanced non-small cell lung cancer with EGFR mutations. Currently, there are several approved third-generation EGFR-TKIs, including Osimertinib, Furmonertinib, and Almonertinib. The way in which different third-generations TKIs bind to the kinase domain is not completely consistent. Therefore, our goal is to explore whether different third-generation EGFR-TKI combinations have synergistic effects and possible mechanisms.
Methods
H1975 cell lines with T790M and L858R mutations, as well as PC9 cell lines with EGFR 19del, were cultured in vitro. We compared the IC50 values and downstream pathway changes of three treatment regimens, including furmonertinib monotherapy, osimertinib combined with furmonertinib, and dual dose furmonertinib, using MTT assay and Western blot methods. We also conducted structural modeling and molecular dynamics simulations. Molecular docking was performed to predict affinity of TKIs to kinase of different combinations.
Results
The results showed that the IC50 value of the combination of osimertinib and furmonertinib was the lowest, lower than the double dose of furmonertinib, indicating a synergistic effect independent of the dose increase effect. The expression levels of phosphorylated Kras (pKras) and phosphorylated ERK (pERK) decreased in the combination group compared to the monotherapy group. Molecular dynamics simulations showed that after furmonertinib covalently binding to the C797 site, the free energy of osimertinib binding to non-covalent binding sites decreased, indicating an increase in affinity, which together inhibited the activation of EGFR mutants.
Conclusions
Our results suggest that the combination of osimertinib and furmonertinib (3+3 mode) has potential synergistic effects, which may be related to an increase in non-covalent binding.
Legal entity responsible for the study
CATO.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.