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

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

Research output: Contribution to journalArticle

264 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2858-2866
Number of pages9
JournalJournal of Clinical Investigation
Volume120
Issue number8
DOIs
Publication statusPublished - Aug 2 2010
Externally publishedYes

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Phosphatidylinositol 3-Kinases
Sirolimus
Neoplasms
Mutation
Precision Medicine
1-Phosphatidylinositol 4-Kinase
Everolimus
Therapeutics
Biomarkers
Clinical Trials
Peptides
Pharmaceutical Preparations
Genes

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Cite this

Di Nicolantonio, F., Arena, S., Tabernero, J., Grosso, S., Molinari, F., Macarulla, T., ... Bardelli, A. (2010). Deregulation of the PI3K and KRAS signaling pathways in human cancer cells determines their response to everolimus. Journal of Clinical Investigation, 120(8), 2858-2866. https://doi.org/10.1172/JCI37539

Deregulation of the PI3K and KRAS signaling pathways in human cancer cells determines their response to everolimus. / Di Nicolantonio, Federica; Arena, Sabrina; Tabernero, Josep; Grosso, Stefano; Molinari, Francesca; Macarulla, Teresa; Russo, Mariangela; Cancelliere, Carlotta; Zecchin, Davide; Mazzucchelli, Luca; Sasazuki, Takehiko; Shirasawa, Senji; Geuna, Massimo; Frattini, Milo; Baselga, José; Gallicchio, Margherita; Biffo, Stefano; Bardelli, Alberto.

In: Journal of Clinical Investigation, Vol. 120, No. 8, 02.08.2010, p. 2858-2866.

Research output: Contribution to journalArticle

Di Nicolantonio, F, Arena, S, Tabernero, J, Grosso, S, Molinari, F, Macarulla, T, Russo, M, Cancelliere, C, Zecchin, D, Mazzucchelli, L, Sasazuki, T, Shirasawa, S, Geuna, M, Frattini, M, Baselga, J, Gallicchio, M, Biffo, S & Bardelli, A 2010, 'Deregulation of the PI3K and KRAS signaling pathways in human cancer cells determines their response to everolimus', Journal of Clinical Investigation, vol. 120, no. 8, pp. 2858-2866. https://doi.org/10.1172/JCI37539
Di Nicolantonio, Federica ; Arena, Sabrina ; Tabernero, Josep ; Grosso, Stefano ; Molinari, Francesca ; Macarulla, Teresa ; Russo, Mariangela ; Cancelliere, Carlotta ; Zecchin, Davide ; Mazzucchelli, Luca ; Sasazuki, Takehiko ; Shirasawa, Senji ; Geuna, Massimo ; Frattini, Milo ; Baselga, José ; Gallicchio, Margherita ; Biffo, Stefano ; Bardelli, Alberto. / Deregulation of the PI3K and KRAS signaling pathways in human cancer cells determines their response to everolimus. In: Journal of Clinical Investigation. 2010 ; Vol. 120, No. 8. pp. 2858-2866.
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