The prognosis of patients with brain metastasis (BM) is poor. In our study, we 
demonstrated that AZD3759, an EGFR tyrosine kinase inhibitors (TKIs) with 
excellent blood-brain barrier (BBB) penetration, combined with radiation 
enhanced the antitumor efficacy in BM model from EGFR mutant (EGFRm) NSCLC. 
Besides, the antitumor activity displayed no difference between radiation 
concurrently with AZD3759 and radiation sequentially with AZD3759. 
Mechanistically, we found that two factors determined the enhanced efficacy: 
cells with EGFRm which were sensitive to AZD3759, and a relative high 
concentration of AZD3759. We have validated mechanisms underlying the 
radiosensitizing effect of AZD3759, which were involved in decreased cell 
proliferation and survival, and suppressed repair of DNA damage. Moreover, our 
study found that AZD3759 inhibited both the non-homologous end joining (NHEJ) 
and homologous recombination (HR) DNA double-strand breaks (DSBs) repair 
pathway, and abrogated the G2/M checkpoint to suppress DNA damage repair. We 
also detected the BBB penetration of AZD3759 when combined with cranial 
radiation. The results showed the BBB penetration of AZD3759 was decreased 
within 24 hr after radiation, however, the free concentration of AZD3759 in 
brain kept at a high level in the context of radiation. In conclusion, our 
findings suggest that AZD3759 combined with radiation enhances the antitumor 
activity in BM from EGFRm NSCLC, this combination therapy may be an effective 
treatment option for BM from EGFRm NSCLC.