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|Ref Type||Journal Article|
|Authors||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|
|Title||Deregulation of the PI3K and KRAS signaling pathways in human cancer cells determines their response to everolimus.|
|Journal||The Journal of clinical investigation|
|Abstract Text||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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|PIK3CA act mut||Advanced Solid Tumor||sensitive||Everolimus||Preclinical - Cell line xenograft||Actionable||In a preclinical study, Afinitor (everolimus) demonstrated efficacy in multiple cancer cell lines in culture and xenograft models with PIK3CA activating mutations (PMID: 20664172).||20664172|
|PIK3CA E545K||breast cancer||sensitive||Everolimus||Preclinical||Actionable||In a preclinical study, breast cancer cell lines harboring a PIK3CA E545K mutation had increased sensitivity to Afinitor (everolimus) in culture (PMID: 20664172).||20664172|
|BRAF V600E PTEN loss||melanoma||predicted - resistant||Everolimus||Case Reports/Case Series||Actionable||In a retrospective analysis, a melanoma patient harboring PTEN loss and BRAF V600E demonstrated resistance to Afinitor (everolimus) treatment, resulting in progressive disease (PMID: 20664172).||20664172|