Work

Phenformin enhances the therapeutic effect of selumetinib in KRAS-mutant non-small cell lung cancer irrespective of LKB1 status

Year: 2017

Type: article

Abstract: // Jun Zhang 1, 2, 3 , Sreenivas Nannapaneni 2 , Dongsheng Wang 2 , Fakeng Liu 2 , Xu Wang 2 , Rui Jin 2 , Xiuju Liu 2 , Mohammad Aminur Rahman 2 , Xianghong Peng 2 , Guoqing Qian 2 , Zhuo G. Chen 2 , Kwok-Kin Wong 4 , Fadlo R. Khuri 1, 2 , Wei Zhou 1, 2 and Dong M. Shin 1, 2 1 Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA 2 Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA 3 Division of Hematology, Oncology and Blood & Marrow Transplantation, Department of Internal Medicine, Holden Comprehensive Cancer Center, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA 4 Dana-Farber Cancer Institute, Harvard Medical School, Dana Building 810B, HIM243, Boston, MA 02115, USA Correspondence to: Dong M. Shin, email: [email protected] Wei Zhou, email: [email protected] Keywords: NSCLC, KRAS, LKB1, phenformin, selumetinib Received: February 28, 2017 Accepted: July 18, 2017 Published: August 01, 2017 ABSTRACT MEK inhibition is potentially valuable in targeting KRAS-mutant non-small cell lung cancer (NSCLC). Here, we analyzed whether concomitant LKB1 mutation alters sensitivity to the MEK inhibitor selumetinib, and whether the metabolism drug phenformin can enhance the therapeutic effect of selumetinib in isogenic cell lines with different LKB1 status. Isogenic pairs of KRAS-mutant NSCLC cell lines A549, H460 and H157, each with wild-type and null LKB1, as well as genetically engineered mouse-derived cell lines 634 ( kras G12D/wt /p53 -/- /lkb1 wt/wt ) and t2 ( kras G12D/wt /p53 -/- / lkb1 -/- ) were used in vitro to analyze the activities of selumetinib, phenformin and their combination. Synergy was measured and potential mechanisms investigated. The in vitro findings were then confirmed in vivo using xenograft models. The re-expression of wild type LKB1 increased phospho-ERK level, suggesting that restored dependency on MEK->ERK->MAPK signaling might have contributed to the enhanced sensitivity to selumetinib. In contrast, the loss of LKB1 sensitized cells to phenformin. At certain combination ratios, phenformin and selumetinib showed synergistic activity regardless of LKB1 status. Their combination reduced phospho-ERK and S6 levels and induced potent apoptosis, but was likely through different mechanisms in cells with different LKB1 status. Finally, in xenograft models bearing isogenic A549 cells, we confirmed that loss of LKB1 confers resistance to selumetinib, and phenformin significantly enhances the therapeutic effect of selumetinib. Irrespective of LKB1 status, phenformin may enhance the anti-tumor effect of selumetinib in KRAS-mutant NSCLC. The dual targeting of MEK and cancer metabolism may provide a useful strategy to treat this subset of lung cancer.

Source: Oncotarget

DOI: 10.18632/oncotarget.19779