LKB1 Deficiency Renders NSCLC Cells Sensitive to ERK Inhibitors
Elisa Caiola1, Alice Iezzi1, Michele Tomanelli1
1Laboratory of Molecular Pharmacology, Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.
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.
Insights
Loss of LKB1 (Serine/threonine kinase 11) in non-small cell lung cancer (NSCLC) sensitizes tumors to ERK inhibitors. This finding offers a new therapeutic strategy for patients with LKB1-mutated NSCLC, who currently lack specific treatments.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Serine/threonine kinase 11 (LKB1/STK11) mutations are prevalent in non-small cell lung cancer (NSCLC), affecting approximately one-third of cases.
- LKB1 activity is also impaired in about half of KRAS-mutated NSCLC, a subgroup with limited therapeutic options.
Purpose of the Study:
- To investigate the therapeutic potential of ERK inhibitors in NSCLC models with LKB1 alterations.
- To determine the efficacy of ERK inhibitors in both LKB1-wild-type and LKB1-mutated NSCLC.
Main Methods:
- Utilized CRISPR/Cas9 technology to systematically delete LKB1 in human NSCLC cell lines.
- Employed isogenic systems and genetically engineered mouse models to assess responses to ERK inhibitors in vitro and in vivo.
Main Results:
- Loss of LKB1 confers sensitivity to ERK inhibitors in both in vitro and in vivo NSCLC models.
- Cells with wild-type LKB1 showed poor response to ERK inhibitors.
- Molecularly, LKB1 loss led to ERK inhibitor-induced inhibition of p90 ribosomal S6 kinase and S6 protein activation, resulting in cytotoxicity.
Conclusions:
- ERK inhibitors represent a viable therapeutic strategy for LKB1-mutated and LKB1/KRAS-mutated NSCLC.
- The differential response based on LKB1 status suggests a favorable toxicity profile for LKB1-mutated tumors.
- Findings are readily translatable to clinical settings, as ERK inhibitors are in clinical development.
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