Enhanced efficacy of AZD3759 and radiation on brain metastasis from EGFR mutant non-small cell lung cancer

Int J Cancer. 2018 Jul 1;143(1):212-224. doi: 10.1002/ijc.31303. Epub 2018 Mar 1.


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.

Keywords: AZD3759; brain metastasis; epidermal growth factor receptor; non-small cell lung cancer; radiation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain Neoplasms / genetics
  • Brain Neoplasms / secondary*
  • Brain Neoplasms / therapy*
  • Carcinoma, Non-Small-Cell Lung / genetics
  • Carcinoma, Non-Small-Cell Lung / therapy*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Proliferation / radiation effects
  • Cell Survival / drug effects
  • Cell Survival / radiation effects
  • Chemoradiotherapy
  • DNA Repair / drug effects
  • DNA Repair / radiation effects
  • ErbB Receptors / genetics
  • Female
  • G2 Phase Cell Cycle Checkpoints / drug effects
  • G2 Phase Cell Cycle Checkpoints / radiation effects
  • Humans
  • Lung Neoplasms / genetics
  • Lung Neoplasms / therapy*
  • Mice
  • Mutation
  • Piperazines / administration & dosage*
  • Piperazines / pharmacology
  • Quinazolines / administration & dosage*
  • Quinazolines / pharmacology
  • Radiation-Sensitizing Agents / administration & dosage*
  • Radiation-Sensitizing Agents / pharmacology
  • Xenograft Model Antitumor Assays


  • AZD3759
  • Piperazines
  • Quinazolines
  • Radiation-Sensitizing Agents
  • EGFR protein, human
  • ErbB Receptors