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

Abstract

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.

Challenges and Novel Opportunities of Radiation Therapy for Brain Metastases in Non-Small Cell Lung Cancer

“…Osimertinib combined with RT in the EGFRT790M mutant NCI-H1975 NSCLC model revealed enhanced antitumor activity as compared to single therapies [ 42 ]. The underlying mechanism was found to be the inhibition of proliferation following irradiation, as well as delayed DNA damage repair [ 43 ]. Mechanistically, AZD3759 radiosensitized NSCLC cells had inhibited both the non-homologous end joining (NHEJ) and homologous recombination (HR) DNA double-strand breaks (DSBs) repair pathway, thus suppressing DNA damage repair.…”

“…Although the effectiveness of concurrent RT and EGFR-TKIs in BMs from NSCLC patients remains inconclusive, results from these trials will reveal whether these strategies are clinically plausible. The development of EGFR targeting agents designed to penetrate the BBB (such as AZD3759) may also change the management of patients with BMs in combination with RT [ 43 ].…”

Adverse effects of chemoradiotherapy on invasion and metastasis of tumor cells

“… 18 DNA repair in tumor cells of patients with brain metastases, after radiotherapy, promotes cell proliferation, survival, metastasis, and drugs that block G 2 /M checkpoint under irradiation disrupt DNA damage repair and inhibit brain metastases. 24 Hence, DNA damage is one of the possible mechanisms, as shown in Fig. 1 , that leads to tumor metastasis caused by chemoradiotherapy.…”

Determination and pharmacokinetic study of AZD‐3759 in rat plasma by ultra performance liquid chromatography with triple quadrupole mass spectrometer

“…It is mainly designed to effectively bypass the blood–brain barrier to address CNS metastasis in NSCLC patients carrying EGFR mutations, such as brain metastasis (BM) and dura mater (or pia mater, leptomeningeal metastases). AZD3759 is currently at a phase I/II research and development stage .…”

“…AZD3759 was tolerable up to 300 mg twice a day, with promising clinical activity in EGFR ‐mutant NSCLC with CNS metastases . The recommended phase 2 dose was defined as 200 mg twice a day, at which level both AZD3759 and the metabolite AZ’1168 could reach efficacious concentrations for target inhibition.…”