像依维莫司这样的药物，能够靶向定位mTOR蛋白，它们被用于治疗一些癌症，但并不是所有的蛋白都会对治疗产生应答。来自意大利都灵大学医学院的一个研究团队已经发现了一种新方法，能帮助预测哪些病人会对这样的药物有反应。海军总医院肿瘤诊疗中心康静波

     确切地说，该研究团队发现，在体外存在基因PIK3CA变异的人类癌细胞会对依维莫司产生应答，而只有当同样存在KRAS基因变异时才没有应答。更为重要的一点是，在一些转移性癌症患者身上，KRAS基因变异的存在与依维莫司疗法的应答相关。研究结果表明，通过观察肿瘤中PIK3CA和KRAS基因的变异，将有可能预测患者对靶向mTOR的药物疗法是否有效。

研究人员表示，这项研究将极有可能改变临床策略，但还需要大量研究来证实这项发现。这项研究结果发布在Journal of Clinical Investigation杂志上。

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.

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.