Abstract
Abstract There are currently no effective targeted therapies for KRAS mutant NSCLC. Combination drug strategies that target downstream pathways activated by mutant KRAS are currently being investigated, however efficacy may be limited by inability to induce a sufficient apoptotic response. MDM-2 (murine double minute 2) is a ubiquitin ligase that negatively regulates p53 function by promoting its degradation. Inhibitors of the MDM2-p53 interaction lead to p53 activation and transcription of genes promoting cell cycle arrest and apoptosis. We investigated the efficacy of combined MEK and MDM2 inhibition for KRAS mutant NSCLC. In KRAS mutant NSCLC cell lines with wild-type p53, pimasertib (MEKi) and SAR405838 (MDM-2i) led to upregulation of BIM and PUMA respectively. Induction of apoptosis and cell cycle arrest correlated with in vitro efficacy, and the combination exhibited marked in vivo activity against KRAS mutant p53 wild-type NSCLC xenograft tumors. These studies provide rationale for future clinical investigation of combined MEK and MDM-2 inhibition for KRAS mutant NSCLC. Citation Format: Aaron N. Hata, Hannah L. Archibald, Maria D. Gomez-Caraballo, Laurent R. DeBussche, Sukhvinder Sidhu, James Watters, Jeffrey A. Engelman. Combined inhibition of MDM2 and MEK for KRAS mutant non-small cell lung cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 741. doi:10.1158/1538-7445.AM2014-741
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