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.
Highlights
KRAS is one of the most commonly mutated oncogenes in non-small cell lung cancer (NSCLC), with a reported frequency of 15–30% [1]
When exploring possible mechanisms for this observation, we found that A549pBabe cells have a very low level of phospho-ERK1/2 (p-ERK1/2) compared to A549LKB1 cells (Figure 1E), suggesting LKB1 inactivation is associated with less dependency on the MEK->extracellular-signal-regulated kinase (ERK)->MAPK signaling pathway, and decreased sensitivity to the MEK inhibitor selumetinib
Through a meta-analysis based on multiple reported studies, as well as our own isogenic cell lines, we have clearly demonstrated that in the setting of KRAS mutation, LKB1 inactivation correlates with decreased response to the MEK inhibitor selumetinib probably through decreased dependency on MEK->ERK->MAPK signaling pathway
Summary
KRAS is one of the most commonly mutated oncogenes in NSCLC, with a reported frequency of 15–30% [1]. Since RAS activates more than a dozen downstream signaling pathways [4], a combination approach was www.impactjournals.com/oncotarget found necessary to achieve durable response [5, 6]. The MEK inhibitor selumetinib was shown initially in a phase II trial to be highly promising in advanced NSCLC with KRAS mutation [9]. This initial signal of efficacy was not confirmed in a recent phase III study, the SELECT-1 trial (NCT01933932). Considering KRAS activates multiple other signaling pathways [4], identifying novel MEK inhibitorbased combination therapies with potential effectiveness in cancer cells with various concomitant mutations is urgently needed. An ideal combination would enhance the therapeutic effect of MEK inhibition (MEKi), have minimal or no added side effects, and be potentially effective against a wide range of concomitant mutations
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