Deregulation of the PI3K and KRAS signaling pathways in human cancer cells determines their response to everolimus

Laboratory of Molecular Genetics, Institute for Cancer Research and Treatment, IRCC, University of Turin Medical School, Turin, Italy.
The Journal of clinical investigation (Impact Factor: 13.22). 08/2010; 120(8):2858-66. DOI: 10.1172/JCI37539
Source: PubMed


Personalized cancer medicine is based on the concept that targeted therapies are effective on subsets of patients whose tumors carry specific molecular alterations. Several mammalian target of rapamycin (mTOR) inhibitors are in preclinical or clinical trials for cancers, but the molecular basis of sensitivity or resistance to these inhibitors among patients is largely unknown. Here we have identified oncogenic variants of phosphoinositide-3-kinase, catalytic, alpha polypeptide (PIK3CA) and KRAS as determinants of response to the mTOR inhibitor everolimus. Human cancer cells carrying alterations in the PI3K pathway were responsive to everolimus, both in vitro and in vivo, except when KRAS mutations occurred concomitantly or were exogenously introduced. In human cancer cells with mutations in both PIK3CA and KRAS, genetic ablation of mutant KRAS reinstated response to the drug. Consistent with these data, PIK3CA mutant cells, but not KRAS mutant cells, displayed everolimus-sensitive translation. Importantly, in a cohort of metastatic cancer patients, the presence of oncogenic KRAS mutations was associated with lack of benefit after everolimus therapy. Thus, our results demonstrate that alterations in the KRAS and PIK3CA genes may represent biomarkers to optimize treatment of patients with mTOR inhibitors.

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Available from: Federica Di Nicolantonio
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    • "In principle, patients harboring PIK3CA mutations or PTEN loss of function, without concomitant KRAS/BRAF mutations, may benefit from targeted treatments against PI3K or PI3K-downstream effectors such as mTOR or AKT [80]; however, emerging clinical data have shown only minimal single-agent activity of such inhibitors at tolerated doses [81-83]. It is likely that mTOR kinase, AKT, pan-PI3K, or isoform-specific PI3K inhibitors will provide greater therapeutic index when combined with RTK inhibitors [84]. "
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    • "In reality not all activating mutations within a given gene are comparable in their effect, as has been shown in other tumour types. For instance, it has been suggested that not all KRAS mutations in colorectal cancer are equally effective in conferring resistance to anti-EGFR antibodies [10]. "
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    Full-text · Article · Jun 2014 · BMC Research Notes
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    • "A second limitation or explanation of our findings is that we do not know the role of drug treatment in suppressing the appearance of mutant tumor cells in the circulation. For example, at the time that 50 of Patient 12’s CTCs showed no mutation, the patient was receiving RAD001 (everolimus), an mTOR inhibitor that may be more active against cells carrying PIK3CA mutations [41]; her CTC count subsequently dropped to zero, perhaps showing response to therapy over time. "
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