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.
Highlights
Lung cancer is the leading cause of cancer deaths worldwide and non-small cell lung cancer (NSCLC) accounts for 80% of all lung cancer cases [1]
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
To check whether the presence of WT or mutated KRAS induced different downstream signaling, we evaluated the activation of PI3K and MAPK pathways at different times after BEZ235 (25 nM) or BKM120 (1 μM)
Summary
Lung cancer is the leading cause of cancer deaths worldwide and non-small cell lung cancer (NSCLC) accounts for 80% of all lung cancer cases [1]. KRAS is one of the most frequently mutated oncogenes in NSCLC and 90% of these mutations affect codon 12, in which the glycine (G) can be replaced with aspartic acid (D), valine (V), or cysteine (C), the G12C substitution being the most frequent. These mutations lead to uncontrolled cell growth, proliferation and survival [4]. KRAS is one of the earliest known oncogenic drivers in NSCLC, effective targeting remains a therapeutic challenge. A specific allosteric inhibitor of G12C mutated KRAS was described, showing promising preclinical results [8]
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