title: Deregulation of the PI3K and KRAS signaling pathways in human cancer cells determines their response to everolimus.
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, 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.
authors.affiliation: Laboratory of Molecular Genetics, Institute for Cancer Research and Treatment, IRCC, University of Turin Medical School, Turin, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Di Nicolantonio
authors.forename: Sabrina
authors.initials: S
authors.lastname: Arena
authors.forename: Josep
authors.initials: J
authors.lastname: Tabernero
authors.forename: Stefano
authors.initials: S
authors.lastname: Grosso
authors.forename: Francesca
authors.initials: F
authors.lastname: Molinari
authors.forename: Teresa
authors.initials: T
authors.lastname: Macarulla
authors.forename: Mariangela
authors.initials: M
authors.lastname: Russo
authors.forename: Carlotta
authors.initials: C
authors.lastname: Cancelliere
authors.forename: Davide
authors.initials: D
authors.lastname: Zecchin
authors.forename: Luca
authors.initials: L
authors.lastname: Mazzucchelli
authors.forename: Takehiko
authors.initials: T
authors.lastname: Sasazuki
authors.forename: Senji
authors.initials: S
authors.lastname: Shirasawa
authors.forename: Massimo
authors.initials: M
authors.lastname: Geuna
authors.forename: Milo
authors.initials: M
authors.lastname: Frattini
authors.forename: José
authors.initials: J
authors.lastname: Baselga
authors.forename: Margherita
authors.initials: M
authors.lastname: Gallicchio
authors.forename: Stefano
authors.initials: S
authors.lastname: Biffo
authors.forename: Alberto
authors.initials: A
authors.lastname: Bardelli
mesh_terms: D045744:Cell Line, Tumor; D058534:Class I Phosphatidylinositol 3-Kinases; D000068338:Everolimus; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D015398:Signal Transduction / Q000187:drug effects*; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases; D018631:ras Proteins / Q000235:genetics*
chemical_list: D058534:Class I Phosphatidylinositol 3-Kinases; D000068338:Everolimus; D047908:Intracellular Signaling Peptides and Proteins; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D016283:Proto-Oncogene Proteins p21(ras); D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; D018631:ras Proteins; C117307:KRAS protein, human; C546842:MTOR protein, human; C484760:PIK3CA protein, human