SCIENTIFIC INNOVATION
Enhanced efficacy of AZD3759 and radiation on brain metastasis from EGFR mutant non-small cell lung cancer
Source:International Journal of Cancer | Author:晨泰医药 | Publish time: 2018-03-01 | 711 Views | Share:


2018年:AZD3759登上国际抗癌联盟(UICC)官方期刊

 

AZD3759联合放疗可以增强EGFR突变型NSCLC脑转移疗效

 

  脑转移患者的预后较差,由于常规药物难以渗透血脑屏障而发挥疗效,故脑转移患者通常需要接受放疗。既往研究发现,对于颅外肿瘤,表皮生长因子受体酪氨酸激酶抑制剂具有放射增敏作用,这表明能够渗透血脑屏障的此类药物如果联合放疗,可能成为脑转移的新疗法。表皮生长因子受体酪氨酸激酶抑制剂AZD3759具有出色的血脑屏障渗透能力,已被证实对表皮生长因子受体突变型非小细胞肺癌脑转移有效,使之成为脑转移放射增敏的理想候选药物。

  201831日,国际抗癌联盟(UICC)官方期刊《国际癌症杂志》在线发表天津医科大学肿瘤医院肿瘤研究所、国家肿瘤临床医学研究中心、山东大学附属省肿瘤医院、山东省医学科学院、阿斯利康亚洲创新医药中心的研究报告,发现AZD3759联合放疗可以增强二者对表皮生长因子受体突变型非小细胞肺癌脑转移的抗肿瘤疗效。该研究通讯作者为山东省肿瘤医院邢力刚教授、中国工程院院士于金明教授。

  该研究首先通过表皮生长因子受体突变型非小细胞肺癌脑转移小鼠模型,证实AZD3759具有优异的血脑屏障渗透能力,联合放疗可以增强抗肿瘤疗效。此外,AZD3759同步放疗与AZD3759序贯放疗相比,抗肿瘤疗效相似。

  通过作用机制分析,该研究发现增强疗效的两个决定因素:表皮生长因子受体突变细胞对AZD3759敏感、相对较高的AZD3759浓度。AZD3759的放射增敏作用机制涉及减少肿瘤细胞的增殖和生存,以及抑制肿瘤细胞DNA损伤的修复(图1)。

  此外,该研究还发现,AZD3759可以同时抑制非同源末端连接(NHEJ)和同源重组(HRDNA双链断裂(DSB)修复通路,并且清除肿瘤细胞分裂间期DNA合成后(G2)进入肿瘤细胞分裂期(M)的检查点,从而抑制肿瘤细胞DNA损伤的修复(图234)。

  该研究还检测了AZD3759联合头颅放疗时的血脑屏障通透性,结果表明虽然放疗后24小时内血脑屏障对AZD3759通透性减少,但是放疗仍使脑组织的AZD3759游离浓度保持于高水平(图56)。

  因此,该研究结果表明,对于表皮生长因子受体突变型非小细胞肺癌脑转移,AZD3759联合放疗可以增强抗肿瘤活性,该联合疗法可能成为表皮生长因子受体突变型非小细胞肺癌脑转移的有效治疗选择。该结果值得开展进一步临床研究,以证实AZD3759联合放疗有效治疗表皮生长因子受体突变型非小细胞肺癌脑转移的潜力。

 

Int J Cancer. 2018 Mar 1. [Epub ahead of print]

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

Li X, Wang Y, Wang J, Zhang T, Zheng L, Yang Z, Xing L, Yu J.

Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China; Shandong Cancer Hospital Affiliated to Shandong University, Shandong Academic of Medical Science, Jinan, China; Asia Innovative Medicines and Early Development, AstraZeneca, Shanghai, China.

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

PMID: 29430654

DOI: 10.1002/ijc.31303

 

1AZD3759联合放疗对表达野生型EGFREGFR突变NSCLC细胞株细胞增殖和生存的作用。

2AZD3759联合放疗所致DNA双链断裂(DSB)作用。

3AZD3759联合放疗对细胞周期和细胞凋亡的作用。

4AZD3759联合放疗对EGFR信号转导通路和DNA损伤应答信号转导的作用。

5AZD3759联合放疗对PC-9脑转移小鼠模型的药物代谢动力学和药物效应动力学。

6AZD3759联合放疗对PC-9脑转移小鼠模型的抗肿瘤活性。