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

J Clin Invest. doi:10.1172/JCI37539.
Copyright © 2010, The American Society for Clinical Investigation.
Research Article
Deregulation of the PI3K and KRAS signaling pathways in human cancer cells determines their response to everolimus
Federica Di Nicolantonio1,2, Sabrina Arena1, Josep Tabernero3, Stefano Grosso4,5, Francesca Molinari6, Teresa Macarulla3, Mariangela Russo1, Carlotta Cancelliere1, Davide Zecchin1, Luca Mazzucchelli6, Takehiko Sasazuki7, Senji Shirasawa8, Massimo Geuna9, Milo Frattini6, José Baselga3, Margherita Gallicchio10, Stefano Biffo4,5 and Alberto Bardelli1,2

1Laboratory of Molecular Genetics, Institute for Cancer Research and Treatment, IRCC, University of Turin Medical School, Turin, Italy.
2FIRC, Institute of Molecular Oncology, Milan, Italy.
3Medical Oncology Department, Vall d’Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain.
4Laboratory of Molecular Histology and Cell Growth, Division of Oncology, San Raffaele Scientific Institute, Milan, Italy.
5DISAV, University of Eastern Piedmont, Alessandria, Italy.
6Laboratory of Molecular Diagnostic, Istituto Cantonale di Patologia, Locarno, Switzerland.
7International Medical Center of Japan, Tokyo, Japan.
8Department of Cell Biology, School of Medicine, Fukuoka University, Fukuoka, Japan.
9Laboratory of Immunopathology, Anatomia Patologica, Ospedale Mauriziano Umberto I, Turin, Italy.
10Department of Anatomy, Pharmacology, and Forensic Medicine, University of Turin, Turin, Italy.

Address correspondence to: Alberto Bardelli, Institute for Cancer Research and Treatment, IRCC, Laboratory of Molecular Genetics, University of Turin Medical School, SP 142, km 3.95, I-10060 Candiolo (Turin), Italy. Phone: 39.011.993.3235; Fax: 39.011.993.3225; E-mail: a.bardelli@unito.it.

Authorship note: Federica Di Nicolantonio and Sabrina Arena contributed equally to this work.


Published July 26, 2010
Received for publication October 6, 2009, and accepted in revised form May 19, 2010.

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.

See the related Commentary PIK3CA and KRAS mutations predict for response to everolimus therapy: now that’s RAD001.

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