Related Experiment Video
Updated: Dec 13, 2025
Evaluation of Amino Acid Consumption in Cultured Bone Cells and Isolated Bone Shafts
Published on: April 13, 2022
Glutaminase Inhibition on NSCLC Depends on Extracellular Alanine Exploitation
Elisa Caiola1, Marika Colombo1, Giovanna Sestito2
1Laboratory of Molecular Pharmacology, Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 20156 Milan, Italy.
Abstract:
Non-small-cell lung cancer (NSCLC) cell lines vary in their sensitivity to glutaminase inhibitors, so it is important to identify the metabolic assets underling their efficacy in cancer cells. Even though specific genetic lesions such as in KRAS and LKB1 have been associated with reliance on glutamine for their metabolic needs, we found no distinction between glutaminase inhibitor CB-839 sensitivity and resistant phenotypes in NSCLC cells with or without these genetic alterations. We demonstrated the close relationship between environmental alanine uptake and catabolism. This response depended on the individual cell's ability to employ alanine aminotransferase (GPT2) to compensate the reduced glutamate availability. It may, therefore, be useful to determine GPT2 levels to predict which NSCLC patients would benefit most from glutaminase inhibitor treatment.
Insights
Glutaminase inhibitors show varied efficacy in non-small cell lung cancer (NSCLC). Alanine uptake and GPT2 levels, not KRAS/LKB1 mutations, predict sensitivity to these metabolic drugs.
Area of Science:
- Oncology
- Cancer Metabolism
- Biochemistry
Background:
- Non-small cell lung cancer (NSCLC) exhibits diverse sensitivity to glutaminase inhibitors.
- Identifying metabolic vulnerabilities is crucial for effective cancer therapy.
- Genetic alterations like KRAS and LKB1 are often linked to glutamine dependency.
Purpose of the Study:
- To investigate the metabolic factors determining glutaminase inhibitor sensitivity in NSCLC.
- To explore the role of alanine metabolism in resistance to glutaminase inhibitors.
- To identify predictive biomarkers for patient response to glutaminase inhibitor therapy.
Main Methods:
- Assessed sensitivity of NSCLC cell lines to the glutaminase inhibitor CB-839.
- Analyzed the impact of KRAS and LKB1 genetic alterations on inhibitor response.
- Investigated the relationship between environmental alanine uptake and cancer cell metabolism.
- Evaluated the role of alanine aminotransferase (GPT2) in compensating for reduced glutamate.
Main Results:
- No significant difference in CB-839 sensitivity was observed between NSCLC cells with or without KRAS/LKB1 mutations.
- A strong correlation was found between environmental alanine uptake and cancer cell catabolism.
- GPT2 expression and activity were critical for cells to utilize alanine and compensate for glutamate deficiency.
- GPT2 levels emerged as a potential predictor of response to glutaminase inhibitors.
Conclusions:
- Glutamine dependency, indicated by KRAS/LKB1 mutations, does not solely determine sensitivity to glutaminase inhibitors in NSCLC.
- Alanine metabolism, specifically GPT2-mediated alanine uptake and catabolism, plays a significant role in NSCLC cell adaptation to glutaminase inhibition.
- Measuring GPT2 levels in NSCLC patients could help predict their response to glutaminase inhibitor treatment, enabling personalized therapy.
