Reference Detail

Ref Type

Journal Article

PMID

(20664172)

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	Vol	Issue	Date	Pages	Journal Short Title
The Journal of clinical investigation	120	8	2010 Aug	2858-66	J Clin Invest

URL

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.

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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
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
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