Abstract 4602: Preclinical evaluation of the AKT inhibitor MK2206 in nasopharyngeal carcinoma cell lines

Abstract

Abstract MK2206 is an allosteric inhibitor of AKT with potent activity in cancer cell lines that exhibit genetic aberrations in the PI3K-AKT-PTEN pathway. AKT is frequently activated in nasopharyngeal carcinoma (NPC), while PIK3CA amplification is found in 40-70% of NPC tissues. The preclinical activity of MK2206 was evaluated in NPC cell lines: HONE-1-EBV, HONE-1, CNE-2, HNE-1, and 2 cell lines with PIK3CA amplifications, HK-1 and C666-1. All 6 cell lines showed increased basal level of activated (p-)AKT(ser473), p-GSK3β, p-mTOR, pi-p70S6K and p-4EBP1, except in C666-1 cells where p-70S6K and p-4EBP1 were weakly expressed. Basal expression of p-MAPK was most pronounced in HK-1, CNE-2 and HONE-1-EBV, and weakly expressed in C666-1 and HONE-1. The effect on cell growth was evaluated by exposing cells to increasing concentrations (conc) of MK2206 (100pM, 2nM, 20nM, 0.2µM, 2µM, 30µM) for up to 72 hrs followed by MTT assay. Over 95% of growth inhibition was achieved in all cell lines with respective IC50 values of: CNE-2=0.39µM, HK-1 = 0.48µM, HONE-1= 1.51µM, C666-1= 1.64µM, HNE-1= 1.92µM, HONE1-EBV= 2.36µM. CNE-2, HONE-1-EBV and C666-1 were selected for assessing the effect on AKT signaling, apoptosis, cell cycle and synergism with chemotherapy. Treatment of these cells with MK2206 at IC50 conc for 15 and 24 hours, resulted in G1 arrest in CNE-2 and HONE-1-EBV, and G2 arrest in C666-1 cells. Apoptosis (increased cleaved PARP) was detected in CNE-2 cells only. MK2206 reduced the expression of p-AKT, p-mTOR, p-BAD, p-FKHD and p-GSK3β in CNE-2, HONE-1-EBV and C666-1 cells, while the level of p-4EBP1 level was significantly reduced in C666-1 and CNE-2 cells only. The effect on p-70S6K expression in all 3 cell lines was minimal. MK2206 increased expression of p-MAPK in HONE1-EBV-1 and C666-1 cells, but not CNE-2 cells. A supra-additive effect on cell growth was observed when cisplatin was added to MK2206, while the effect of adding paclitaxel to MK2206 was minimal in all 3 cell lines. Our result suggests that MK2206 has activity in NPC in vitro. The increased expression of p-MAPK observed in some cell lines suggests the presence of compensatory MAPK activation as described with mTOR inhibitors in other cancers. MK-2206 is currently under clinical investigation in recurrent NPC. 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 4602. doi:1538-7445.AM2012-4602