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- W1480075781 abstract "AACR Annual Meeting-- Apr 18-22, 2009; Denver, COVandetanib is a tyrosine kinase inhibitor (TKI) with activity against vascular endothelial growth factor receptor 2 (VEGFR-2), epidermal growth factor receptor (EGFR) and REarranged during Transfection (RET) receptor signaling, which has recently completed phase III trials in the second-line setting of advanced non-small cell lung cancer as monotherapy and in combination with docetaxel or pemetrexed. The mechanisms of acquired resistance to vandetanib remain unclear, so we established in vitro vandetanib-resistant PC-9/VanR cells from PC-9, a vandetanib-sensitive lung adenocarcinoma cell line harboring an EGFR exon 19 deletion (E746-A750) mutation, by chronic exposure to this agent. PC-9/VanR cells were 50-fold more resistant to vandetanib than PC-9 cells in vitro and showed emergence of the EGFR T790M mutation (AACR 2008, Abstract #678). Compared with PC-9 cells, PC-9/VanR cells showed modest MET amplification (1.5-fold) and similar VEGFR-2 inhibition by vandetanib. Of note, in PC-9/VanR cells, phosphorylated MET was suppressed by an irreversible EGFR-TKI, suggesting that MET activity in PC-9/VanR cells is dependent on EGFR signaling, and that MET signaling is not the primary mechanism of resistance to vandetanib. In vivo , vandetanib inhibited the growth of PC-9/VanR tumor xenografts model through anti-angiogenic effects mediated by VEGFR-2 inhibition. Vandetanib exhibited similar antitumor efficacy against two additional established human lung adenocarcinoma tumor cell xenografts harboring EGFR T790M mutations (H1975, RPC-9). In contrast, gefitinib showed less in vivo activity against xenografts harboring an EGFR T790M mutation. These data provide a strong scientific rationale for investigating vandetanib in clinical settings where acquired resistance through emergence of EGFR T790M mutations limits the effectiveness of gefitinib.Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr LB-216." @default.
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- W1480075781 date "2009-05-01" @default.
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- W1480075781 title "Abstract #LB-216: Effects of vandetanib on lung adenocarcinoma cells harboring an EGFR T790M mutation in vivo" @default.
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