Abstract 2476: P53 is potential predictive biomarker for combination therapy of epidermal growth factor receptor (EGFR) and MET inhibitors in non-small cell lung cancer (NSCLC) with wild-type EGFR
Authors: Hong Yun Kyoung , Kim Sun Mi , Sung Ji Hee , Duong Hong-Quan , Kim Joo-Hang , Cho Byoung Chul 
Published: August 2012

Abstract
Receptor tyrosine kinase (RTK) systems, such as hepatocyte growth factor (HGF) and its receptor MET and epidermal growth factor (EGF) and its receptor EGFR, are known to be expressed in non-small cell lung cancer (NSCLC) and play an important role in the progression of NSCLC. Recent research shows that co-inhibition of MET and EGFR signaling results in more robust antitumor activity, relative to either alone, although the mechanisms of this synergism are not clear. P53, a tumor suppressor gene, is a potent regulator of apoptosis which is induced by DNA damage. The dysregulation of p53 protein is related to both oncogenesis and drug resistance. The purpose of this study was to investigate the mechanisms of synergistic antitumor effects of an EGFR inhibitor (gefitinib) and two different MET inhibitors (SU11274 and tivantinib [ARQ 197]) and to potentially define the role of P53 function as a predictive biomarker for the observed synergy. P53 wild-type (A549 and H460) cells and P53 null-type (H358 and H1299) cells without met gene amplification or EGFR mutation were used. Combined gefitinib and SU11274 or tivantinib induced profound growth inhibitory effects and apoptosis in cell lines harboring wild-type P53, but not in cells harboring null P53. SU11274 or tivantinib appeared to abrogate the P53/Mdm2 interaction, concomitantly reducing P53-ubiquitination followed by protein stabilization. Treatment with gefitinib resulted in the translocation of P53 from cytosol to nucleus. In P53 wild-type cells, the combination treatment of SU11274 or ARQ197 with gefitinib induced more robust apoptosis than single agent treatment, presumably through up-regulation of p53 target genes (FAS, Bax and PUMA). Furthermore, inhibition of P53 expression in A549 cells using siRNA significantly reduced apoptosis and downregulated mRNA and protein expression of FAS, PUMA and Bax upon combined treatment with gefitinib and SU11274. Overexpression of wild-type P53 in H1299 cells enhanced growth inhibition and apoptosis by combined gefitinib and SU11274 treatment through up-regulation of FAS, PUMA and Bax and restoration of caspase activation. In an A549 xenograft model, the combination of gefitinib and SU11274 (or tivantinib) effectively shrunk tumor volume and also induced apoptosis more effectively than either treatment alone. In conclusion, P53 plays an essential role in determining synergistic efficacy of combination therapy with pharmacological EGFR and MET inhibition in NSCLC with wild type EGFR. The validation of the predictive value of P53 mutation is warranted in appropriate ongoing clinical trials of combination therapy in advanced NSCLC patients with wild-type EGFR.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2476. doi:1538-7445.AM2012-2476