Different metabolic responses to PI3K inhibition in NSCLC cells harboring wild-type and G12C mutant KRAS

// Elisa Caiola 1, * , Laura Brunelli 2, * , Mirko Marabese 1 , Massimo Broggini 1 , Monica Lupi 3 , Roberta Pastorelli 2 1 Laboratory of Molecular Pharmacology, Department of Oncology, IRCCS-Istituto di Ricerche Farmacologiche “Mario Negri”, Milan, Italy 2 Protein and Gene Biomarkers Unit, Laboratory of Mass Spectrometry, Department of Environmental Health Sciences, IRCCS-Istituto di Ricerche Farmacologiche “Mario Negri”, Milan, Italy 3 Laboratory of Cancer Pharmacology, Department of Oncology, IRCCS-Istituto di Ricerche Farmacologiche “Mario Negri”, Milan, Italy * These authors have contributed equally to this work Correspondence to: Massimo Broggini, email: massimo.broggini@marionegri.it Roberta Pastorelli, email: roberta.pastorelli@marionegri.it Keywords: KRAS, NSCLC, metabolomics, BEZ235, BKM120 Received: November 24, 2015      Accepted: May 22, 2016      Published: June 06, 2016 ABSTRACT 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.