Different metabolic responses to PI3K inhibition in NSCLC cells harboring wild-type and G12C mutant KRAS
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Elisa Caiola1,*, Laura Brunelli2,*, Mirko Marabese1, Massimo Broggini1, Monica Lupi3, Roberta Pastorelli2
1Laboratory of Molecular Pharmacology, Department of Oncology, IRCCS-Istituto di Ricerche Farmacologiche “Mario Negri”, Milan, Italy
2Protein and Gene Biomarkers Unit, Laboratory of Mass Spectrometry, Department of Environmental Health Sciences, IRCCS-Istituto di Ricerche Farmacologiche “Mario Negri”, Milan, Italy
3Laboratory of Cancer Pharmacology, Department of Oncology, IRCCS-Istituto di Ricerche Farmacologiche “Mario Negri”, Milan, Italy
*These authors have contributed equally to this work
Massimo Broggini, email: [email protected]
Roberta Pastorelli, email: [email protected]
Keywords: KRAS, NSCLC, metabolomics, BEZ235, BKM120
Received: November 24, 2015 Accepted: May 22, 2016 Published: June 06, 2016
KRAS mutations in non-small-cell lung cancer (NSCLC) patients are considered a negative predictive factor and indicate poor response to anticancer treatments. KRAS mutations lead to activation of the PI3K/akt/mTOR pathway, whose inhibition remains a challenging clinical target. Since the PI3K/akt/mTOR pathway and KRAS oncogene mutations all have roles in cancer cell metabolism, we investigated whether the activity of PI3K/akt/mTOR inhibitors (BEZ235 and BKM120) in cells harboring different KRAS status is related to their metabolic effect. Isogenic NSCLC cell clones expressing wild-type (WT) and mutated (G12C) KRAS were used to determine the response to BEZ235 and BKM120. Metabolomics analysis indicated the impairment of glutamine in KRAS-G12C and serine metabolism in KRAS-WT, after pharmacological blockade of the PI3K signaling, although the net effect on cell growth, cell cycle distribution and caspase activation was similar. PI3K inhibitors caused autophagy in KRAS-WT, but not in KRAS-G12C, where there was a striking decrease in ammonia production, probably a consequence of glutamine metabolism impairment.
These findings lay the grounds for more effective therapeutic combinations possibly distinguishing wild-type and mutated KRAS cancer cells in NSCLC, exploiting their different metabolic responses to PI3K/akt/mTOR inhibitors.
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