AZD3759, a BBB-penetrating EGFR inhibitor for the treatment of EGFR mutant NSCLC with CNS metastases

Yang, Zhenfan; Guo, Qiuli; Wang, Yingchun; Chen, Kan; Zhang, Lin; Cheng, Ziqiang; Xu, Yanping; Yin, Xiaolu; Bai, Yu; Rabbie, Sarit C.; Kim, Dong Wan; Ahn, Myung Ju; Yang, James Chih Hsin; Zhang, Xiaolin

doi:10.1126/scitranslmed.aag0976

Cited by 91 publications

(73 citation statements)

References 40 publications

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“…AEE788 and dacomitinib, which have no previous reports regarding their efflux transporter liability, were shown to be substrates of both/ either P-gp and/or Bcrp in this study (see the DA values in Table 4). The K p,brain in TKO for AZD3759 was similar to the value in wild-type, with a DA of 1.56, which indicates neither P-gp nor Bcrp plays a major role in the brain distribution of AZD3759, as was previously reported (Zeng et al, 2015;Yang et al, 2016). In conclusion, seven out of eight EGFR inhibitors investigated in the current study were shown to be substrates of both/either P-gp and/or Bcrp based on the DA calculated with the brain partition coefficients in wild-type and TKO mice, and AZD3759 is the only exception that is not a substrate of both P-gp and Bcrp.…”

Section: Discussionsupporting

confidence: 77%

Brain Distribution of a Panel of Epidermal Growth Factor Receptor Inhibitors Using Cassette Dosing in Wild-Type and Abcb1/Abcg2-Deficient Mice

Kim¹,

Laramy²,

Mohammad³

et al. 2019

Drug Metab Dispos

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Tyrosine kinase inhibitors that target the epidermal growth factor receptor (EGFR) have had success in treating EGFR-positive tumors, including non-small-cell lung cancer (NSCLC). However, developing EGFR inhibitors that can be delivered to the brain remains a challenge. To identify optimal compounds for brain delivery, eight EGFR inhibitors [afatinib, 6-[4-[(4-ethylpiperazin-and vandetanib] were evaluated for distributional kinetics using cassette dosing with the ultimate goal of understanding the brain penetrability of compounds that share the same molecular target in an important oncogenic signaling pathway for both primary brain tumors (glioblastoma) and brain metastases (e.g., NSCLC). Cassette dosing was validated by comparing the brain-to-plasma ratios obtained from cassette-dosing to discrete-dosing studies. The brain-to-blood partition coefficients (K p,brain ) were calculated following cassette dosing of the eight EGFR inhibitors. The comparison of K p,brain in wild-type and transporter-deficient mice confirmed that two major efflux transporters at the blood-brain barrier (BBB), P-glycoprotein and breast cancer resistance protein, play a crucial role in the brain distribution of seven out of eight EGFR inhibitors. Results show that the prediction of brain distribution based on physicochemical properties of a drug can be misleading, especially for compounds subject to extensive efflux transport. Moreover, this study informs the choice of EGFR inhibitors, i.e., determining BBB permeability combined with a known target potency, that may be effective in future clinical trials for brain tumors.

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Section: Discussionsupporting

confidence: 77%

Brain Distribution of a Panel of Epidermal Growth Factor Receptor Inhibitors Using Cassette Dosing in Wild-Type and Abcb1/Abcg2-Deficient Mice

Kim¹,

Laramy²,

Mohammad³

et al. 2019

Drug Metab Dispos

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“…AZD3759 represents a novel class of EGFR‐TKI, which is not a substrate of the efflux transporters P‐gp or BCRP. This compound, which was specifically developed to achieve high exposure both in the plasma and in the CNS by penetrating the BBB, is under investigation for the treatment of CNS metastases from NSCLC . AZD3759 has an unbound brain exposure:unbound plasma ratio of 0.86, indicating similar free exposure in the brain and plasma .…”

Section: Egfr‐tkismentioning

confidence: 99%

Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors for Central Nervous System Metastases from Non-Small Cell Lung Cancer

Ahluwalia¹,

Becker

Levy

2018

The Oncologist

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Historically, treatment options for patients who develop central nervous system (CNS) metastases have been limited and associated with poor outcomes. The development of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) has improved outcomes for patients with EGFR-mutated disease, and emerging data have demonstrated the ability of these drugs to cross the blood-brain barrier and elicit significant intracranial responses. Recent studies have indicated a role for next-generation EGFR-TKIs, such as osimertinib, in the treatment of CNS metastases. In the context of an evolving treatment paradigm, treatment should be individualized to the patient and requires a multidisciplinary approach.

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“…In contrast to the negative clinical results in BM, radiosensitizing effect of EGFR‐TKIs was reported in extracranial tumors in both clinical and preclinical settings, suggesting the potential of combining a BBB‐penetrating agent with radiation for BM. AZD3759 was an EGFR‐TKIs with good BBB penetration in both preclinical and clinical settings, and showed promising activity in patients with central nervous system (CNS) metastasis as monotherapy . In our study, we evaluated the potential of AZD3759 in combination with radiation in a BM model in mice, and explored the mechanism underneath.…”

Section: Introductionmentioning

confidence: 99%

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

Wang

et al. 2018

Intl Journal of Cancer

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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.

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AZD3759, a BBB-penetrating EGFR inhibitor for the treatment of EGFR mutant NSCLC with CNS metastases

Cited by 91 publications

References 40 publications

Brain Distribution of a Panel of Epidermal Growth Factor Receptor Inhibitors Using Cassette Dosing in Wild-Type and Abcb1/Abcg2-Deficient Mice

Brain Distribution of a Panel of Epidermal Growth Factor Receptor Inhibitors Using Cassette Dosing in Wild-Type and Abcb1/Abcg2-Deficient Mice

Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors for Central Nervous System Metastases from Non-Small Cell Lung Cancer

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

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