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Eur J Cancer. 2017 Oct;84:184-192. doi: 10.1016/j.ejca.2017.07.037. Epub 2017 Aug 17.

Apatinib enhances antitumour activity of EGFR-TKIs in non-small cell lung cancer with EGFR-TKI resistance.

Author information

1
Department of Radiation Medicine, School of Basic Medical Science, Peking University, Beijing 100191, China.
2
Orthopedic Department, Peking University International Hospital, Beijing 102206, China.
3
Department of Tumor Chemotherapy and Radiation Sickness, Peking University Third Hospital, Beijing 100191, China.
4
Department of Radiation Medicine, School of Basic Medical Science, Peking University, Beijing 100191, China. Electronic address: wangjd@bjmu.edu.cn.
5
Department of Tumor Chemotherapy and Radiation Sickness, Peking University Third Hospital, Beijing 100191, China. Electronic address: liang.dr@163.com.

Abstract

BACKGROUND:

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs)-rechallenged therapy for EGFR-mutant non-small cell lung cancer (NSCLC) patients who acquired resistance showed moderate efficacy. Considering the high interrelation between EGFR and vascular endothelial growth factor/vascular endothelial growth factor receptor (VEGF/VEGFR) pathways, we firstly evaluated EGFR-TKI combined with apatinib (a highly selective VEGFR2 inhibitor) in EGFR-TKI-resistant model and patients.

METHODS:

Effects of apatinib, gefitinib and gefitinib plus apatinib were assessed on four NSCLC cell lines (A549 with wild-type EGFR, H1975 harbouring L858R and T790M, H1650 and HCC827 harbouring E746_A750 deletion) and xenograft model of acquired resistance that was established by injecting H1975 cells. Furthermore, we retrospectively evaluated EGFR-TKI rechallenge with apatinib in 16 patients.

RESULTS:

Gefitinib plus apatinib strengthened the effect of gefitinib and apatinib alone on the four NSCLC cell lines, and H1975 was the most susceptible one. Co-administration delayed the tumour growth than mono-therapy in the xenograft model and had better effect on inhibiting the activation of EGFR and VEGFR2 and expression of CD31 (an angiogenesis marker) and vascular endothelial growth factor A (an important pro-angiogenesis factor in the tumour microenvironment). Changes in protein expression of protein kinase B/mammalian target of rapamycin and extracellular signal-regulated kinase pathways demonstrated the potent inhibitory effect on the pro-survival signalling pathways by combined therapy. EGFR-TKI rechallenge with apatinib achieved a median progression-free survival of 4.60 months (95% confidence interval, 2.23-12.52 months) in the patients.

CONCLUSIONS:

Apatinib significantly potentiated the antitumour effect of gefitinib in NSCLC with T790M-related EGFR-TKI resistance both in vivo and vitro. EGFR-TKI rechallenge with apatinib might represent a new option for NSCLC with T790M or unknown resistance mechanism.

KEYWORDS:

Apatinib; EGFR; Gefitinib; NSCLC; VEGFR

PMID:
28822888
DOI:
10.1016/j.ejca.2017.07.037
[Indexed for MEDLINE]

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