Apatinib enhances antitumour activity of EGFR-TKIs in non-small cell lung cancer with EGFR-TKI resistance. (October 2017)

• Record Type: Journal Article
• Authors: Li, Fang; Zhu, Tengjiao; Cao, Baoshan; Wang, Jiadong; Liang, Li
• Is Part Of: European journal of cancer. Volume 84(2017)
• Page Start: 184
• Page End: 192
• Publication Date: 2017-10
• Subjects: NSCLC -- Apatinib -- Gefitinib -- EGFR -- VEGFR; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Cancer; Tumors; Electronic journals; Periodicals; Electronic journals; 616.994
• DOI: 10.1016/j.ejca.2017.07.037
• Languages: English
• ISSNs: 0959-8049

Abstract

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. Highlights: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) rechallenge showed moderate efficacy for non-small cell lung cancer (NSCLC) patients with acquired resistance. Relation between EGFR and vascular endothelial growth factor pathways indicates potential of combined therapy. Sensitivity was restored in H1975 (T790M resistant) cells by gefitinib plus apatinib. EGFR-TKI combined with apatinib achieved good efficacy in resistant NSCLC patients.