Abstract 3620: Efficacy of Vandetanib on EGFR mutant lung cancer cells with PTEN loss

Abstract

Abstract Introduction EGFR gene is frequently mutated in non-small cell lung cancer (NSCLC) of never smokers, especially in Asian ethnicity. The mutations often predict dramatic response to EGFR-tyrosine kinase inhibitors (TKIs) like gefitinib. PTEN is a tumor-suppressor gene deactivating PI3K in downstream of EGFR signaling. Approximately 2% to 9% in NSCLC tumors were considered to be PTEN loss. PTEN loss and EGFR mutation co-occurred in 1 out of 24 EGFR mutant patients with lung adenocarcinoma (Sos, et al. Cancer Res 69, 2009). PTEN loss was considered to represent primary or acquired resistance to EGFR-TKIs. Therefore, a new strategy is needed to break through for the resistance due to PTEN loss. Objective We clarify the effectiveness of vandetanib, EGFR and vascular endothelial growth factor receptor (VEGFR) inhibitor, against lung cancer cell lines harboring EGFR mutations with PTEN loss. Materials and methods: Two EGFR mutant (deletion in exon19) NSCLC cell lines, PC-9 (PTEN wild type) and NCI-H1650 (PTEN loss) were used. Other two cell lines with PTEN loss, prostate cancer cell line (PC-3) and glioblastoma cell line (U-87MG) were also examined. We transfected intact PTEN gene into H1650 cells and knocked down PTEN expression in the PC-9 cells using shRNA. Antiproliferative activity was determined by MTT assay in terms of 50% inhibitory concentration (IC50) values. We also examined the effectiveness of the drugs (15 mg/kg/day) in xenograft model. Protein expression profile was examined by Western blotting. Expression of VEGFR mRNA levels was also assessed by RT-PCR. Results PC-9 cells were more resistant to vandetanib (IC50: 0.08 μM) than to gefitinib (IC50: 0.01 μM). However, mean IC50 values of vandetenib were significantly lower than those of gefitinib against H1650 cells (2 μM vs 25 μM), PC-3 cells (8 μM vs 25 μM), and U87MG cells (6 μM vs 28 μM) with PTEN loss. EGFR downstream signals including pAKT, pMAPK, and pSTAT3, and VEGFR were not different in the H1650 cells treated with vandetanib or gefitinib. In the xenograft model using H1650 cells, vandetanib was also more effective than gefitinib. Although PTEN transfected H1650 cells did not restore sensitiveness to gefitinib in vitro, the xenograft tumors responded to gefitinib as well as vandetanib. Knockdown of PTEN lead six times more resistance to gefitinib in PC-9 cells. Conclusion PTEN loss may play a role to determine the sensitivity to gefitinib in NSCLC with EGFR mutations. Vandetanib is more effective in NSCLC with EGFR mutation and PTEN loss. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3620.