LKB1 Deficiency Renders NSCLC Cells Sensitive to ERK Inhibitors
| Autor: | Elisa Bonaldi, Michele Tomanelli, Alice Iezzi, Marina Chiara Garassino, Elisa Caiola, Marika Colombo, Edoardo Micotti, Massimo Broggini, Arianna Scagliotti, Lucia Minoli, Mirko Marabese, Eugenio Scanziani, Federica Guffanti |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Pulmonary and Respiratory Medicine MAPK/ERK pathway congenital hereditary and neonatal diseases and abnormalities Lung Neoplasms STK11 Antineoplastic Agents Protein Serine-Threonine Kinases medicine.disease_cause Serine 03 medical and health sciences 0302 clinical medicine Carcinoma Non-Small-Cell Lung Ulixertinib Humans Medicine Cytotoxic T cell Threonine skin and connective tissue diseases Mutation Kinase business.industry 030104 developmental biology Oncology 030220 oncology & carcinogenesis Cancer research business |
| Zdroj: | Journal of Thoracic Oncology. 15:360-370 |
| ISSN: | 1556-0864 |
| DOI: | 10.1016/j.jtho.2019.10.009 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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