Background: Combining with docetaxel, the MEK inhibitor selumetinib holds the promise in treating KRAS mutant non-small cell lung cancer (NSCLC). However, a previous co-clinical trial based on genetically engineered mouse model (GEMM) suggested that concomitant loss of LKB1 might confer primary resistance. Since LKB1 inactivation was recently shown to sensitize NSCLC cells to the metabolism drug phenformin, which may also activate AMPK in LKB1 wild-type NSCLC, we therefore investigated whether phenformin could enhance the therapeutic effect of selumetinib in KRAS mutant NSCLC with different status of LKB1. Methods: NSCLC cell lines harboring RAS/RAF mutations that were tested with selumetinib were identified from literature to study the correlation of LKB1 status with selumetinib sensitivity. Then, the isogenic derivatives of A549 cell line namely A549^LKB1 (stably expressing wild-type LKB1) and A549^pBabe (empty vector, LKB1 deficient) were used for actual studies of selumetinib, phenformin, their combination and dosing sequence. Phenformin was also investigated in GEMM derived cell lines 634 (Kras^G12D/wt/p53^-/-/LKB1^wt/wt) and t2 (Kras^G12D/wt/p53^-/-/LKB1^-/-). Results: 29 NSCLC cell lines were identified which showed concomitant LKB1 mutation significantly correlated with selumetinib resistance (IC50>1uM, p=0.0025). Consistently, A549^LKB1 cells were more sensitive to selumetinib. In contrast, A549^pBabe (as well as t2) cells showed stronger response to phenformin. Their synergism was observed in both the proliferation and colony formation assays, and confirmed via CalcuSyn calculation. While phenformin helped induce much more robust apoptosis in A549^pBabe cells, it also activated AMPK and potently enhanced the inhibition of S6 phosphorylation by selumetinib in A549^LKB1cells. Interestingly, when the drugs were applied sequentially in single agent, selumetinib followed by phenformin was ~ 3 folds more efficient in inducing apoptosis than the reverse order. Conclusions: Phenformin may synergize the anti-tumor effect of selumetinib in KRAS mutant NSCLC irrespective of the LKB1 status. Their combination offers a potential new therapy for this subtype of NSCLC.