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

• Authors: Fadlo Khuri, Emory University; Georgia Chen, Emory University; Xu Wang, Emory University; Jun Zhang, Emory University; Sreenivas Nannapaneni, Emory University; Dongsheng Wang, Emory University; Fakeng Liu, Emory University; Rui Jin, Emory University; Xiuju Liu, Emory University; Mohammad Rahman, Emory University; XiangHong Peng, Emory University; Guoqing Qian, Emory University; Kwok-Kin Wong, Harvard Med Sch; Wei Zhou, Emory University; Dong Shin, Emory University
• Journal Title: Oncotarget
• Volume: Volume 8, Number 35
• Publisher: Impact Journals | 2017-08-29, Pages 59008-59022
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.18632/oncotarget.19779
• Subjects: Biology, Microbiology; Health Sciences, Oncology
• Keywords: Science & Technology; Life Sciences & Biomedicine; Oncology; Cell Biology; NSCLC; KRAS; LKB1; phenformin; selumetinib; MEK INHIBITORS; LACTIC-ACIDOSIS; BREAST-CANCER; TUMOR-GROWTH; IN-VITRO; METFORMIN; ACTIVATION; PATHWAY; RAS; SURVIVAL

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.