Capturing the metabolomic diversity of KRAS mutants in non-small-cell lung cancer cells
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Laura Brunelli1,*, Elisa Caiola2,*, Mirko Marabese2, Massimo Broggini2 and Roberta Pastorelli1
1 Protein and Gene Biomarkers Unit, Department of Environmental Health Sciences, IRCCS-Istituto di Ricerche Farmacologiche “Mario Negri”, Milan, Italy
2 Laboratory of Molecular Pharmacology, Department of Oncology, IRCCS-Istituto di Ricerche Farmacologiche “Mario Negri”, Milan, Italy
* The authors contributed equally to this work
Roberta Pastorelli, email:
Massimo Broggini, email:
Keywords: KRAS, mutations, NSCLC, metabolomics, mass-spectrometry
Received: February 18, 2014 Accepted: May 12, 2014 Published: May 12, 2014
In non-small-cell lung cancer (NSCLC), one-fifth of patients have KRAS mutations, which are considered a negative predictive factor to first-line therapy. Evidence is emerging that not all KRAS mutations have the same biological activities and possible remodeling of cell metabolism by KRAS activation might complicate the scenario. An open question is whether different KRAS mutations at codon-12 affect cellular metabolism differently with possible implications for different responses to cancer treatments.
We applied an explorative mass spectrometry-based untargeted metabolomics strategy to characterize the largest possible number of metabolites that might distinguish isogenic NSCLC cells overexpressing mutated forms of KRAS at codon-12 (G12C, G12D, G12V) and the wild-type. The glutamine deprivation assay and real-time PCR were used to confirm the involvement of some of the metabolic pathways highlighted.
Cell clones indicated distinct metabolomic profiles in KRAS wild-type and mutants. Clones harboring different KRAS mutations at codon-12 also had different metabolic remodeling, such as a different redox buffering system and different glutamine-dependency not driven by the transcriptional state of enzymes involved in glutaminolysis.
These findings indicate that KRAS mutations at codon-12 are associated with different metabolomic profiles that might affect the responses to cancer treatments.
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