LKB1 Deficiency Renders NSCLC Cells Sensitive to ERK Inhibitors. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer

Elisa Caiola, Alice Iezzi, Michele Tomanelli, Elisa Bonaldi, Arianna Scagliotti, Marika Colombo, Federica Guffanti, Edoardo Micotti, Marina Chiara Garassino, Lucia Minoli, Eugenio Scanziani, Massimo Broggini, Mirko Marabese

Research output: Contribution to journalArticlepeer-review

Abstract

INTRODUCTION: Serine/threonine kinase 11 (LKB1/STK11) is one of the most mutated genes in NSCLC accounting for approximately one-third of cases and its activity is impaired in approximately 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 (WT) 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 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 the molecular level, in the absence of LKB1, ERK inhibitors induced 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. Because ERK inhibitors are already in clinical development, our findings could be easily translatable to the clinic. Importantly, the lack of effect in cells expressing WT LKB1, predicts that treatment of LKB1-mutated tumors with ERK inhibitors should have a favorable toxicity profile.
Original languageEnglish
Pages (from-to)360-370
Number of pages11
JournalJournal of Thoracic Oncology
Volume15
Issue number3
DOIs
Publication statusPublished - 2020

Keywords

  • Humans
  • Mutation
  • *NSCLC
  • *Antineoplastic Agents/therapeutic use
  • *Carcinoma, Non-Small-Cell Lung/drug therapy/genetics
  • *ERK inhibitor
  • *LKB1/STK11
  • *Lung Neoplasms/drug therapy/genetics
  • *SCH772984
  • *Ulixertinib
  • Protein-Serine-Threonine Kinases/genetics

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