Atorvastatin overcomes gefitinib resistance in KRAS mutant human non-small cell lung carcinoma cells

J Chen,L Yue,J Hou,X Wen,B Liu,C Zhang,X Zhang,D Liu,H Bi,J Yuan,H Shi,J Liu

doi:10.1038/cddis.2013.312

Abstract

The exact influence of statins on gefitinib resistance in human non-small cell lung cancer (NSCLC) cells with KRAS mutation alone or KRAS/PIK3CA and KRAS/PTEN comutations remains unclear. This work found that transfection of mutant KRAS plasmids significantly suppressed the gefitinib cytotoxicity in Calu3 cells (wild-type KRAS). Gefitinib disrupted the Kras/PI3K and Kras/Raf complexes in Calu3 cells, whereas not in Calu3 KRAS mutant cells. These trends were corresponding to the expression of pAKT and pERK in gefitinib treatment. Atorvastatin (1 μM) plus gefitinib treatment inhibited proliferation, promoted cell apoptosis, and reduced the AKT activity in KRAS mutant NSCLC cells compared with gefitinib alone. Atorvastatin (5 μM) further enhanced the gefitinib cytotoxicity through concomitant inhibition of AKT and ERK activity. Atorvastatin could interrupt Kras/PI3K and Kras/Raf complexes, leading to suppression of AKT and ERK activity. Similar results were also obtained in comutant KRAS/PTEN or KRAS/PIK3CA NSCLC cells. Furthermore, mevalonate administration reversed the effects of atorvastatin on the Kras/Raf and Kras/PI3K complexes, as well as AKT and ERK activity in both A549 and Calu1 cells. The in vivo results were similar to those obtained in vitro. Therefore, mutant KRAS-mediated gefitinib insensitivity is mainly derived from failure to disrupt the Kras/Raf and Kras/PI3K complexes in KRAS mutant NSCLC cells. Atorvastatin overcomes gefitinib resistance in KRAS mutant NSCLC cells irrespective of PIK3CA and PTEN statuses through inhibition of HMG-CoA reductase-dependent disruption of the Kras/Raf and Kras/PI3K complexes.

Highlights

Persistent activation of PI3K signaling by the PIK3CA oncogenic mutation is sufficient to abrogate gefitinib-induced apoptosis of nonsmall cell lung cancer (NSCLC) cells.[4]
Mutations in the KRAS gene have been found in 20–30% of NSCLC14 and believed to be critically involved in gefitinib resistance
Our data show that transfection of mutant KRAS plasmids into WT NSCLC cell line Calu[3] confers gefitinib resistance in these cells

Summary

Introduction

Persistent activation of PI3K signaling by the PIK3CA oncogenic mutation is sufficient to abrogate gefitinib-induced apoptosis of NSCLC cells.[4]. Received 21.5.13; revised 17.7.13; accepted 29.7.13; Edited by M Agostini cancer[10] and celexocib in prostate cancers.[11] Our previous study indicates that atorvastatin sensitizes NSCLC cells to carboplatin through inhibition of AKT activation.[12] the exact influence of statins on gefitinib resistance in KRAS mutant NSCLC cells remains unclear. This study was designed to explore the mechanism underlying gefitinib resistance and the effect of atorvastatin on gefitinib sensitivity in KRAS mutant NSCLC cells. The results indicate that gefitinib fails to disrupt the direct interaction of Kras with PI3K and Raf, contributing to its resistance in KRAS mutant NSCLC cells. Our data suggest that atorvastatin can overcome gefitinib resistance in NSCLC cells harboring KRAS mutation irrespective of PIK3CA or PTEN status

Methods

Results

Conclusion