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Deregulation of the PI3K and KRAS signaling pathways in human cancer cells determines their response to everolimus
Federica Di Nicolantonio, … , Stefano Biffo, Alberto Bardelli
Federica Di Nicolantonio, … , Stefano Biffo, Alberto Bardelli
Published July 26, 2010
Citation Information: J Clin Invest. 2010;120(8):2858-2866. https://doi.org/10.1172/JCI37539.
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Research Article

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

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Abstract

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, α 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.

Authors

Federica Di Nicolantonio, Sabrina Arena, Josep Tabernero, Stefano Grosso, Francesca Molinari, Teresa Macarulla, Mariangela Russo, Carlotta Cancelliere, Davide Zecchin, Luca Mazzucchelli, Takehiko Sasazuki, Senji Shirasawa, Massimo Geuna, Milo Frattini, José Baselga, Margherita Gallicchio, Stefano Biffo, Alberto Bardelli

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Figure 3

Effect of everolimus on RAS/PI3K signaling in PIK3CA and KRAS mutant cells.

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Effect of everolimus on RAS/PI3K signaling in PIK3CA and KRAS mutant cel...
PIK3CA mutant ME-180 and HKe-3 cells were transduced with either empty or KRAS D13–expressing lentiviral vectors. All cells were treated for 30 minutes with everolimus (50 nM), and the corresponding lysates were blotted with total RSK1/RSK2/RSK3, phospho–p90RSK (Ser380), total S6K1, phospho-S6K1 (Thr389), total AKT, phospho-AKT (Ser473), total ERK1/2 and phospho-ERK1/2 antibodies, phospho-rpS6 (Ser235–236), and total rpS6. Vinculin was included as a loading control.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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