Oncotarget

Research Papers:

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

Jun Zhang, Sreenivas Nannapaneni, Dongsheng Wang, Fakeng Liu, Xu Wang, Rui Jin, Xiuju Liu, Mohammad Aminur Rahman, Xianghong Peng, Guoqing Qian, Zhuo G. Chen, Kwok-Kin Wong, Fadlo R. Khuri, Wei Zhou and Dong M. Shin _

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Oncotarget. 2017; 8:59008-59022. https://doi.org/10.18632/oncotarget.19779

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Abstract

Jun Zhang1,2,3, Sreenivas Nannapaneni2, Dongsheng Wang2, Fakeng Liu2, Xu Wang2, Rui Jin2, Xiuju Liu2, Mohammad Aminur Rahman2, Xianghong Peng2, Guoqing Qian2, Zhuo G. Chen2, Kwok-Kin Wong4, Fadlo R. Khuri1,2, Wei Zhou1,2 and Dong M. Shin1,2

1Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA

2Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA

3Division 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

4Dana-Farber Cancer Institute, Harvard Medical School, Dana Building 810B, HIM243, Boston, MA 02115, USA

Correspondence to:

Dong M. Shin, email: dmshin@emory.edu

Wei Zhou, email: wzhou2@emory.edu

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 (krasG12D/wt/p53-/-/lkb1wt/wt) and t2 (krasG12D/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.


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