LKB1 deficiency renders non-small-cell lung cancer cells sensitive to ERK inhibitors.: ERK inhibitors in LKB1 mutated NSCLC

Abstract Background Liver kinase B1 (LKB1/STK11) is one of the most mutated genes in non-small-cell lung cancer (NSCLC) accounting for about one third of cases and its activity is impaired in about half of KRAS mutated NSCLC. At present, these patients cannot benefit from any specific therapy. Methods Through CRISPR/Cas9 technology, we systematically deleted LKB1 in both wild-type and KRAS-mutated human NSCLC cells. By using these isogenic systems together with genetically engineered mouse models we investigated the cell response to ERK inhibitors both in vitro and in vivo. Results In all the systems used here, the loss of LKB1 creates a vulnerability and renders these cells particularly sensitive to ERK inhibitors both in vitro and in vivo. The same cells expressing a wt LKB1 poorly respond to these drugs. At molecular level, ERK inhibitors induced, in the absence of LKB1, a marked inhibition of p90 ribosomal S6 kinase activation, which in turn abolished S6 protein activation, promoting the cytotoxic effect. Conclusions This work shows that ERK inhibitors are effective in LKB1 and LKB1/KRAS mutated tumors, thus offering a therapeutic strategy for this prognostically unfavorable subgroup of patients. Since ERK inhibitors are already in clinical development, our findings could be easily translatable to the clinic. Importantly, the lack of effect in cells expressing wild-type LKB1, predicts that treatment of LKB1 mutated tumors with ERK inhibitors should have a favorable toxicity profile.