科學創新
Enhanced efficacy of AZD3759 and radiation on brain metastasis from EGFR mutant non-small cell lung cancer
來源:International Journal of Cancer | 作者:晨泰醫藥 | 發布時間: 2018-03-01 | 945 次瀏覽 | 分享到:

2018年:AZD3759登上國際抗癌聯盟(UICC)官方期刊

 

AZD3759聯合放療可以增強EGFR突變型NSCLC腦轉移療效

 

  腦轉移患者的預后較差,由于常規藥物難以滲透血腦屏障而發揮療效,故腦轉移患者通常需要接受放療。既往研究發現,對于顱外腫瘤,表皮生長因子受體酪氨酸激酶抑制劑具有放射增敏作用,這表明能夠滲透血腦屏障的此類藥物如果聯合放療,可能成為腦轉移的新療法。表皮生長因子受體酪氨酸激酶抑制劑AZD3759具有出色的血腦屏障滲透能力,已被證實對表皮生長因子受體突變型非小細胞肺癌腦轉移有效,使之成為腦轉移放射增敏的理想候選藥物。

  201831日,國際抗癌聯盟(UICC)官方期刊《國際癌癥雜志》在線發表天津醫科大學腫瘤醫院腫瘤研究所、國家腫瘤臨床醫學研究中心、山東大學附屬省腫瘤醫院、山東省醫學科學院、阿斯利康亞洲創新醫藥中心的研究報告,發現AZD3759聯合放療可以增強二者對表皮生長因子受體突變型非小細胞肺癌腦轉移的抗腫瘤療效。該研究通訊作者為山東省腫瘤醫院邢力剛教授、中國工程院院士于金明教授。

  該研究首先通過表皮生長因子受體突變型非小細胞肺癌腦轉移小鼠模型,證實AZD3759具有優異的血腦屏障滲透能力,聯合放療可以增強抗腫瘤療效。此外,AZD3759同步放療與AZD3759序貫放療相比,抗腫瘤療效相似。

  通過作用機制分析,該研究發現增強療效的兩個決定因素:表皮生長因子受體突變細胞對AZD3759敏感、相對較高的AZD3759濃度。AZD3759的放射增敏作用機制涉及減少腫瘤細胞的增殖和生存,以及抑制腫瘤細胞DNA損傷的修復(圖1)。

  此外,該研究還發現,AZD3759可以同時抑制非同源末端連接(NHEJ)和同源重組(HRDNA雙鏈斷裂(DSB)修復通路,并且清除腫瘤細胞分裂間期DNA合成后(G2)進入腫瘤細胞分裂期(M)的檢查點,從而抑制腫瘤細胞DNA損傷的修復(圖234)。

  該研究還檢測了AZD3759聯合頭顱放療時的血腦屏障通透性,結果表明雖然放療后24小時內血腦屏障對AZD3759通透性減少,但是放療仍使腦組織的AZD3759游離濃度保持于高水平(圖56)。

  因此,該研究結果表明,對于表皮生長因子受體突變型非小細胞肺癌腦轉移,AZD3759聯合放療可以增強抗腫瘤活性,該聯合療法可能成為表皮生長因子受體突變型非小細胞肺癌腦轉移的有效治療選擇。該結果值得開展進一步臨床研究,以證實AZD3759聯合放療有效治療表皮生長因子受體突變型非小細胞肺癌腦轉移的潛力。

 

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聯合放療對表達野生型EGFREGFR突變NSCLC細胞株細胞增殖和生存的作用。


2AZD3759聯合放療所致DNA雙鏈斷裂(DSB)作用。 


3AZD3759聯合放療對細胞周期和細胞凋亡的作用。

4AZD3759聯合放療對EGFR信號轉導通路和DNA損傷應答信號轉導的作用。


5AZD3759聯合放療對PC-9腦轉移小鼠模型的藥物代謝動力學和藥物效應動力學。


6AZD3759聯合放療對PC-9腦轉移小鼠模型的抗腫瘤活性。



 
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