Lung cancer is the most common cancer worldwide and, because of its high fatality, it also represents the most common cause of cancer related deaths. Non-small-cell lung cancers (NSCLCs) constitute about 85% of lung cancers and the 5-year survival rate is currently below 20%. Only a limited number of NSCLC patients, carrying alterations in specific genes, can benefit from small molecules therapies, highlighting the need for new treatment strategies to improve the outcome of the remaining patients.
KRAS is among the most frequently mutated oncogene in NSCLC and 90% of the mutations affect codon 12, with the G12C substitution being the most frequent. KRAS mutations in NSCLC are supposed to be associated to a poor prognosis and poor response to chemotherapy. Despite KRAS being one of the earliest known oncogenic drivers in NSCLC, it is considered practically undruggable. Mutations in KRAS gene lead to the activation of PI3K/akt/mTOR pathway, whose effective inhibition remains a challenging clinical target.
Since PI3K/akt/mTOR pathway and KRAS oncogene mutations have both a role 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 effect at metabolic level.A targeted metabolomics approach was applied to a robust and well characterized isogenic system to profile the metabolic adaptations occurring in KRAS-G12C and KRAS-wild type (WT) cells in response to treatment with BEZ235 and BKM120. KRAS-G12C and KRAS-WT harboring cells displayed similar sensitivities to BEZ235 and BKM120 treatments. Metabolomics analysis indicated that the different KRAS isoforms induced a distinct metabolic response to PI3K inhibitor treatments. In particular, impairment of glutamine and serine metabolism, in KRAS-G12C and KRAS-WT respectively, was observed after pharmacological blockade of the PI3K signaling. In addition, PI3K inhibitors caused autophagy in KRAS-WT isoform, but not in KRAS-G12C, where a striking decreased in ammonia production was found as probable consequence of glutamine metabolism impairment. At doses relevant for autophagy, differences in apoptosis and cell cycle phase distribution were not detected in KRAS-WT and KRAS-G12C clones.
These preliminary results would set the basis for more effective therapeutic combinations possibly exploiting the different metabolic response to PI3K/akt/mTOR inhibitors in NSCLC cells harboring a different KRAS status.
Citation Format: Elisa Caiola, Laura Brunelli, Mirko Marabese, Roberta Pastorelli, Monica Lupi, Massimo Broggini. PI3K pathway inhibition induces a different metabolic response in NSCLC cells harboring WT and G12C mutant KRAS. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 226.